Derivatives and analogs of galanthamine

ABSTRACT

New compounds of general formula I

This application is a continuation of U.S. Ser. No. 09/980,025, filedMar. 18, 2002, the contents of which are hereby incorporated byreference.

This invention relates to new substituted benzofuran derivatives,process for their production, their salts as well as the use for

-   -   a) Treatment of Alzheimer's disease,    -   b) treatment of Parkinson's disease,    -   c) treatment of Huntington's disease (chorea),    -   d) treatment of multiple sclerosis,    -   e) treatment of amyotrophic lateral sclerosis,    -   f) treatment of epilepsy,    -   g) treatment of the sequelae of stroke,    -   h) treatment of the sequelae of cranio-cerebral trauma,    -   i) treatment and prophylaxis of the sequelae of diffuse oxygen        and nutrient deficiency in the brain, as they are observed after        hypoxia, anoxia, asphyxia, cardiac arrest, poisonings, as well        as in the case of complications in difficult deliveries of        infants or in the case of anesthesia,    -   j) especially also prophylactic treatment of apoptotic        degeneration in neurons that were or are damaged by local        radiotherapy or chemotherapy of brain tumors, and    -   k) treatment of bacterial meningitis and    -   l) treatment of diseases with apoptotic components, especially        in the wake of an amyloid-associated cell degeneration,    -   m) treatment of diabetes mellitus, especially if the disease is        accompanied by amyloid degeneration of islet cells.

The new derivatives and analogs of galanthamine according to theinvention increase the muscular power and the perseverance of Alzheimerpatients.

The new compounds according to the invention are those of generalformula I

in which the substituents have the meanings that are explained below:

R₁ and R₂ are the same or different and mean:

a) hydrogen, F, Cl, Br, I, CN, NC, OH, SH, NO₂, SO₃H, PO₃H, NH₂, CF₃,OSO₂(CH₂) CF₃, in which n is equal to 0, 1 or 2), OSO₂-aryl, OSO₂-vinylor OSO₂-ethinyl;

b) a low (C₁-C₆), optionally branched, optionally substituted (Ar)alkyl,(Ar)alkoxy group, cycloalkyl or cycloalkyloxy group;

c) an amino group, which optionally is substituted by one or twoidentical or different low (C₁-C₆), optionally branched, optionallysubstituted (Ar)alkyl or (Ar)alkylcarbonyl or (Ar)alkoxycarbonyl groupsor an amino group which exhibits a cyclic substitution in the form of apyrrolidine, piperidine, morpholine, thiomorpholine, piperazine,homopiperazine radical that is substituted in any case,

d) a COOH, COO(Ar)alkyl, CO-amino, with the definition of the aminogroup as in the last paragraph under c) or a CHOH(Ar)alkyl group;

e) a —(CH₂)nX (in which X═Br, Cl, F or I), —(CH₂)_(n)OH, —(CH₂) CHO,—(CH₂)_(n)COOH, —(CH₂)_(n)CN, —(CH₂)_(n)NC, —(CH₂)_(n)COalkyl,—(CH₂)_(n)COaryl group, in which n means 1-4;

f) a —(CH₂) vinyl, (CH₂)_(n)ethinyl group, or (CH₂)_(n)cycloalkyl groupin which n describes 0, 1 or 2, and cycloalkyl describes an aliphaticring of the ring size of 3-7;

g) a C₃-C₆-substituted alkenyl group (optionally substituted with H, F,Br, Cl, CN, CO₂alkyl, COalkyl, COaryl);

h) a C₃-C₆-substituted alkinyl group (optionally substituted with H, F,Br, Cl, CN, CO₂alkyl, COalkyl, COaryl); or

i) R¹ and R² together mean —CH═CH—CH═CH—, —O(CH₂)_(n)O— (n=1 to 3),—CH═CH-A1 or —CH2—CH2-A1, whereby NH, O or S can stand for Al;

R₃ has the same meaning as R₁, especially OH and OCH₃ and in addition

R₂ and R₃ together mean -A₂(CH₂)_(n)A₂, in which n is 1 to 3 and A₂means two identical or different radicals that are selected from NH, Oor S;

R₄ and R₅ are either

a) both hydrogen, or

b) a combination of hydrogen or an (Ar)alkyl, (Ar)alkenyl or (Ar)alkinylgroup with

-   -   i) OR₆, in which R₆ means hydrogen, a low (C₁-C₁₀, optionally        branched or substituted) alkyl group or cycloalkyl group, a        C₃-C₁₀ substituted silyl group (for example, triethylsilyl,        trimethylsilyl, t-butyldimethylsilyl or dimethylphenylsilyl), a        C₂-C₁₀ α-alkoxyalkyl group, for example tetrahydropyranyl,        tetrahydrofuranyl, methoxymethyl, ethoxymethyl,        (2-methoxypropyl), ethoxyethyl, phenoxymethyl or        (1-phenoxyethyl);    -   ii) O—CS—NHR₆ (thiourethane), in which R₆ has the        above-mentioned meaning    -   iii) O—CO—NHR₇ with the meaning below:    -   iv) O—CO—HR₆, in which R₆ has the above-mentioned meaning,        especially ester with the substitution pattern of amino acids        (both enantiomers), such as    -   v) NR₇R₇, in which two substituents R₇ are the same or different        and mean hydrogen, a low (C₁-C₄), optionally branched or cyclic        alkyl group, or the two substituents R₇ together are        —(CH₂)_(n−), in which n is 3 to 5;    -   vi) NH—COR₆ (amide), in which R₆ has the above-mentioned        meaning;    -   vii) S—R₆, in which R₆ is hydrogen or a low (C₁-C₁₀), optionally        branched, optionally substituted (Ar)alkyl group, and in which        R₆ has the above-mentioned meaning;    -   viii) SO_(n)R₈, in which n is 0, 1 or 2, in which R₈ is a        (C₁-C₁₀), optionally branched or cyclic, optionally substituted        (Ar)alkyl group.

If R₄ is hydrogen, R₅ can be OH, CN, CO₂-alkyl, CONR_(a)R_(b), in whichR_(a) is hydrogen, a low (C₁-C₆), optionally branched, cyclic alkylgroup that is substituted in any case, and R_(b) is hydrogen, a low(C₁-C₆), optionally branched or substituted alkyl group, or R_(a)+R_(b)together are —(CH₂)_(n)—, in which n means 2 to 6, or—(CH₂)_(n)E(CH₂)_(n)—, in which E is the same as NH, N-alkyl, O, or S,and n is 0 to 5, aryl (phenyl or naphthyl), 6-π heterocycle, (such as,for example, imidazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl,oxadiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl andsubstituted variants thereof), or imidazolinyl, thiazolinyl oroxazolinyl.

For the case that R₅ is not hydrogen, R₄ can also be OH.

R₄ and R₅ together can be carbonyl (═O), hydrazone (═N—NH—R₉, ═N—NR₉R₁₀or oxime (═N—OR₁₀), in which R₉ is hydrogen, a low (C₁-C₆), optionallybranched or cyclic, optionally substituted (Ar)alkyl- or(Ar)alkylcarbonyl-, (Ar)alkylcarbonyloxy group or a sulfonic acid group,such as tosyl or mesyl, and R₁₀ is hydrogen, a low (C₁-C₆), optionallybranched or cyclic, optionally substituted (Ar)alkyl- or(Ar)alkylcarbonyl group, a sulfonic acid group, such as a tosyl group ormesyl group.

R₄ and R₅ together can be substituents of the type

in which Y₁, Y₂ are the same or different and mean O, S, NH or N—R₉(free valences are in any case hydrogen), or for the case that Y₁ is NHand Y₂ is N—R₉, R₄ and R₅ can be connected by —(CH 2)_(n)— (n=2, 3, or4).

G₁: —(CH₂)_(x)—, in which x is 1 or 2;

G₂: —(CH₂)_(y)—, in which y is 0 to 2;

G₃: —(CH₂)_(z)—, in which z is 0 to 3, is carbonyl or thiocarbonyl,provided that x+y+z together are at least 2 and at most 4 or in which G₃means —CH(OH)— or —C(OH)═.

G₁ and G₂ together or separately can also mean:

—C(R₁₁R₁₂)—, in which R₁₁ and R₁₂ mean hydrogen, OH, a low, optionallybranched or cyclic, optionally substituted (Ar)alkyl, aryl, (Ar)alkyloxyor aryloxy group or together an alkylspiro group (C₃-C₇ spiro ring) orG₁ and G₂ together mean

in which m is 1 to 7.

W can have the following meanings:

-   -   a) CR₁₃R₁₄, in which R₁₃ means hydrogen and R₁₄ means the        radicals —(CH₂)_(n)NR₇R₇ or —CO—NR₇R₇ or —COOR₇, whereby n can        assume the values 0 to 2 and R₇ is as defined above, or R₇R₇        form a ring by —(CH₂)_(n) (in which n is 3 to 5), whereby        substituents R₁₃ and R₁₄ can be exchanged.    -   b) N-Phenyl (whereby the phenyl radical optionally is        substituted with fluorine, bromine, chlorine, (C₁-C₄) alkyl, CO₂        alkyl, CN, CONH₂, or alkoxy) or N-thien-2 or 3-yl, or N-fur-2 or        3-yl or N-1,3,5-triazinyl, whereby the triazine radical can then        be substituted with C₁, OR₆ or NR₇R₇, and R₆ or R₇ have the        meaning indicated above;    -   c) One of the substituents that is presented below        in which I means no bond or —(CH₂)_(n)—, with n=0 to 3,        carbonyl, thiocarbonyl O, S, —SO— or SO₂, R₆ has the meaning        that is indicated above, and in addition, Q is defined as        —(CH2)n-M⁺-(CH2)m, whereby n=0 to 4 and m=0 to 4 and M⁺        represents alkinyl, alkenyl, disubstituted phenyl, disubstituted        thiophene, disubstituted furan, disubstituted pyrazine,        disubstituted pyridazine, a peptide spacer L or a heterocyclic        spacer HS, whereby this definition of the spacer is defined in        addition by the following graphic formulas        in which R₁₅ means the side chain of D-, L-, D, L-aminoacids or        unnatural amino acids, and for the case of n>1, R₁₅ in the        individual radicals in each case means the same or a different        side chain of D-, L-, D, L-amino acids or unnatural amino acids,        whereby these formulas are defined such that atom N in addition        to Q is connected in each case to G2 and G3 of formula I;

d) W can also be connected to a tricyclic substituent (Tr) via spacer Q,whereby the tricyclic substituents are defined by the following graphicformulas,

and these formulas are defined such that atom N in addition to Q isconnected in each case with G2 and G3 of formula I, and Q and Z have themeaning indicated under c).

The tricyclic substituent (Tr) means a tricyclic ring system, with atleast one heterocyclic ring as a ring component and a binding site to acarbon atom of an anellated benzene ring thereof, whereby Tr optionallyis substituted at least in one place, in which ring A is an optionallysubstituted benzene ring and one of rings B and C is an optionallysubstituted heterocyclic ring and the other can contain a substituted 4-to 14-membered, preferably a 5- to 7-membered ring, which can containone or more heteroatoms in the ring. The benzene ring is optionallyfurther substituted in at least one place, whereby these substituentscan be halogens, such as fluorine and chlorine, halo-C₁-C₃ alkyl groups,such as trifluoromethyl, C₁-C₃alkyl groups, such as methyl, C₁-C₃ alkoxygroups, such as methoxy, and the hydroxy group, whereby halogens, suchas fluorine, are preferred.

Heterocyclic ring B or C that is optionally substituted is, for example,a 4- to 14-membered ring, preferably a 5- to 7-membered ring. At leastone heteroatom of the heterocyclic ring (1 to 3 heteroatoms arepossible) can be nitrogen, oxygen, sulfur. In particular, rings B and Care pyridine, pyrazine, pyrimidine, imidazole, furan, thiophene,pyrrolidine, piperidine, hexamethylethylenimine, tetrahydrofuran,piperazine, morpholine and thiomorpholine, whereby 5- to 7-memberednonaromatic rings, which can have one or two heteroatoms that are thesame or different, are preferred.

Ring B or C can also be a non-aromatic, heterocyclic ring that contains1-3 heteroatoms, such as nitrogen, oxygen or sulfur, and nonaromaticheterocyclic rings with a nitrogen atom, and another heteroatom, whichis nitrogen, oxygen or sulfur.

“5- to 8-membered rings B or C” are 5- to 8-membered heterocyclic oralicyclic rings or carbon rings, which are substituted at least in oneplace. These 5- to 8-membered carbon rings can be a benzene ring or asaturated or unsaturated ring, for example, benzene, cyclopentane,cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane,cycloheptene and cycloheptadiene.

If rings B or C contain at least one heteroatom (e.g., 1-3 heteroatoms,such as nitrogen, oxygen, sulfur, etc.), i.e., if ring B or C is aheterocyclic ring, it may or may not be aromatic. Such aromaticheterocyclic rings are, for example, pyridine, furan, thiophene.Preferred nonaromatic, heterocyclic rings are the above-indicatedexamples of rings B or C.

Accordingly, tricyclic substituent Tr can be a condensed benzene ring ofgeneral formula

Examples in this respect are:

Carbazole,

-   1,2,3,4-4a,9a-hexahydrocarbazole,-   9,10-dihydroacridine,-   1,2,3,4-tetrahydroacridine,-   10,11-dihydro-5H-dibenz[b,f]azepine,-   5,6,11,12-tetrahydrodibenz[b,g]azocine,-   6,11-dihydro-5H-dibenz[b,e,]azepine,-   6,7-dihydro-5H-dibenz[c,e]azepine,-   5,6,11,12-tetrahydrodibenz[b,f]azocine,-   dibenzofuran,-   9H-xanthene,-   1-O-11-dihydrobenz[b,f]oxepin,-   6,11-dihydrobenz[b,e]oxepin,-   6,7-dihydro-5H-dibenz[b,g]oxacine,-   dibenzothiophene,-   9H-thioxanthene,-   10,11-dihydrodibenzo[b,f]thiepin,-   6,11-dihydrodibenzo[b,e]thiepin,-   6,7-dihydro-5H-dibenzo[b,g]thiocin,-   10H-phenothiazine,-   10H-phenoxazine,-   5,10-dihydrophenazine,-   10,11-dibenzo[b,f]-[1,4]thiazepine,-   2,3,5,6,11,11a-hexahydro-1H-pyrrolo[2,1-b][3]benzazepine,-   1-O,11-dihydro-5H-dibenzo[b,e][1,4]diazepine,-   5,11-dihdyrodibenz[b,e][1,4]oxazepine,-   5,11-dihydrodibenzo[b,f][1,4]thiazepine,-   10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine,-   1,2,3,3a,8,8a-hexahydropyrrolo[2,3b]indole.

Tricyclic substituent Tr can be a condensed benzene ring of generalformula

and can mean, for example:

-   1H,3H-Naphth[1,8-cd][1,2]oxazine,-   naphth[1,8-de]-1,3-oxazine,-   naphth[1,8-de]-1,2-oxazine,-   1,2,2a,3,4,5-hexahydrobenz[cd]indole,-   2,3,3a,4,5,6-hexahydro-1H-benzo[de]quinoline,-   4H-pyrrolo[3,2,1-ij]quinoline,-   1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline,-   5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline,-   1H,5H-benzo[ij]quinolizine,-   2,3,6,7-tetrahydro-1H,5H-benzo[ij]quinolizine,-   azepino[3,2,1-hi]indole,-   1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole,-   1H-pyrido[3,2,1-jk][1]benzazepine,-   5,6,7,8-tetrahydro-1H-pyrido[3,2,1-jk][1]benzazepine,-   1,2,56,7,8-hexahydro-5H-pyrido[3,2,1-jk][1]benzazepine,-   2,3-dihydro-1H-benz[de]isoquinoline,-   1,2,3,4,4a,5,6,7-octahydronaphth[1,8-bc]azepine,-   2,3,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine.

Tricyclic substituent Tr can be a condensed benzene ring of generalformula

Examples of these compounds are:

-   1,2,3,5,6,7-Hexahydrobenzo[1,2-b:4,5b′]dipyrrole,-   1,2,3,5,6,7-hexahydrocyclopent[f]indole,-   1,2,3,6,7,8-hexahydrocyclopentan[e]indole or-   2,3,4,7,8-hexahydro-1H-cyclopenta[f]quinoline.

Tricyclic substituent Tr can be a condensed benzene ring of generalformula

Examples of this are:

-   1,2,3,6,7,8-Hexahydrocyclopent[e]indole or-   2,3,4,7,8,9-hexahydro-1H-cyclopenta[f]quinoline.

Additional examples of tricyclic substituents Tr are condensed benzenerings of the following formulas, whereby the binding site to Q can takeup the space of any hydrogen atom:

In addition, Tr can be a cyclic or bicyclic hydrocarbon which isreferred to by the following formula:

In addition, each substituent Tr can be substituted by one or moresubstituents R₁, whereby the definition of substituent R₁ is the same asin formula I.

e) In addition, W can mean —NH—, —S—, —SO— or —SO₂—.

In addition, the invention relates to compounds of general formula II

in which D stands for NH, N-alkyl, N-acyl, oxygen or sulfur, and inwhich substituents R₁ to R₁, G₁ to G₃ and W can have the meanings thatare indicated above in general formula I.

In addition, the invention relates to compounds of general formula III

in which X—R₁₆ is a substituent in which X is oxygen or sulfur and R₁₆is hydrogen or a low (C₁-C₁₀), optionally branched or cyclic, optionallysubstituted (Ar)alkyl group, and in which substituents R₁ to R₅, G₁ toG₃ and W can have the meanings that are indicated above in generalformula I.

The invention extends to compounds of general formula IV

in which W represents CH or N, and R₁₈ and R₁₉ mean hydrogen, alkyl,aryl or aralkyl, and in which the C atoms that carry substituents R₁₈and R₁₉ are linked to one another via a single bond or a double bond andin which substituents R₁ to R₅ as well as G₁ and G₃ have the meaningsthat are indicated above in general formula I.

It is preferred if in the compound of general formula IV substituent Wis nitrogen and/or substituent C₁ is —(CH₂)_(x)—, in which x is equal to1 or 2 and C means —(CH₂)_(y)—, in which y is equal to 0 to 2, providedthat x+y together mean at least 2 and at most 4.

Separation of Optical Isomers from rac. Norgalanthamine:

In addition, the invention includes a process for chiral separation of(6R)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef][2benzazepin-6-ol(norgalanthamine) (4)

The separation of (+) and (−) isomers is carried out by fractionatedcrystallization in such a way that

-   -   a solution or suspension of the optical isomer mixture in which        3 to 50× the amount is added to or introduced into    -   a solvent, such as water, methanol, ethanol, propanol,        isopropanol, acetone or mixtures of this solvent, mainly        methanol    -   with the equimolar amount or excess chiral acid (unsubstituted,        (+) or (−) tartaric acid, citric acid, lactic acid, preferably        (+)—O,O-di-p-toluoyl tartaric acid that is substituted in one or        more places and that is dissolved in one of the above-mentioned        solvents—and the solution or suspension of the optical isomer        mixture is added,    -   that the solution is inoculated with crystals produced from the        natural (−) galanthamine derivatives and chiral organic acids,        such as (+)—O,O-di-p-toluoyl tartaric acid,    -   and is allowed to stand at −40 to +20 degrees, preferably 0        degrees for 2-24 hours or longer,    -   that the formed crystals are filtered and dried,    -   then mixed with excess NH₄OH and extracted with an organic        solvent, such as chloroform, methylene chloride, ethyl acetate,        butyl acetate, diethyl ether, t-butylmethyl ether, dibutyl        ether, petroleum ether, xylene, benzene, toluene or similar        solvents, and the corresponding (−) norgalanthamine is isolated        by distillation of the solvent.

In this process, concentration by evaporation of the mother liquor,uptake of excess NH₄OH, extraction with an organic solvent (as indicatedabove) and concentration by evaporation yield additional fractions ofnorgalanthamine, from which in the same way as above, the (+)norgalanthamine can be produced with chiral organic acids, such as(−)—O,O-di-p-toluoyl tartaric acid.

The products that are obtained according to the invention can bepurified by a suitable process, for example, sublimation, fractionatedcrystallization or chromatography.

Among the compounds according to the invention, especially the compoundsthat are mentioned below are considered:

In the survey below, “AchE” means acetylcholinesterase, “BchE” meansbutyrylcholinesterase, “hr” means human recombinant, “mE” meanspre-incubation of the enzyme with inhibitor, and “IC₅₀” meansconcentration, in which 50% inhibition takes place. IC50 IC50 Patent(AChE, (BChE, Example Substance mE, hr) mE, hr) Laboratory Number CodeIC50 IC50 Code Patent Substanz- Structure (AChE, (BChE, Labor- Beispiel-Code Struktur mE, hr) mE, hr) Code Nummer SPH-1118

100 200 Ro 22 77 SPH-1146

1,2 3,6 TK 66/1 136 / SPH-1149

0,2 0,21 HM 104 137 SPH-1162

200 Cl 2-1, CB 19 138 SPH-1184

0,2 0,6 LCz 225/1 139 SPH-1191

0,35 4,4 LCz 205 140 SPH-1196

5,2 5 TK 36-2 30 SPH-1163

200 0,47 MH 7-1-1 35 SPH-1199

200 2,3 MH 25-1 102 SPH-1200

200 17 MH 30-1 88 SPH-1201

46 0,6 MH-29-1 105 SPH-1202

200 5,2 MH-28-1 104 SPH-1203

MH-26-1 103 SPH-1204

200 200 MH 31-2 89 SPH-1205

70 2,4 MH 33 90 SPH-1206

78 2,5 MH 38-1 91 SPH-1207

47 0,7 MH 39-1 92 SPH-1208

200 25 CB 2 141 SPH-1209

31 20 CB 5 142 SPH-1210

200 43 CB 4 143 SPH-1211

23 30 CB 13, CB 29 27 SPH-1213

6 10 TK 96/3 71 SPH-1214

4,2 200 CB 34, CB 34-2 19 SPH-1215

70 200 CB 33 23 SPH-1217

9,5 17 CB 28 40 SPH-1218

25 0,54 CB 30 8 SPH-1219

28,5 200 CB 36 31 SPH-1220

7,2 21 CB 41 45 SPH-1221

4,8 200 CB 45 20 SPH-1222

6,7 200 CB 46 22 SPH-1227

40 6 HM 38 144 SPH-1228

200 200 CB 43 15 SPH-1229

38 30 CB 52 9 SPH-1230

CB 53 13 SPH-1231

33 200 CB 49 21 SPH-1232

36 200 CB 50 26 SPH-1233

200 200 CB 51 16 SPH-1234

66 200 CB 56 10 SPH-1235

3,4 11 CB 42 46 SPH-1236

21 200 CB 48 28 SPH-1237

24 200 CB 47 24 SPH-1242

70 40 CB 55 17 SPH-1243

40 200 0358 14 SPH-1244

7,6 36 CB 57 12 SPH-1245

25 200 CB 59 11 SPH-1246

17,5 20 MR 16 18 SPH-1247

2,4 4 MR 17 48-Stufel SPH-1248

40 90 MR 7 34 SPH-1249

45 26 MR 13 43 SPH-1250

200 95 MH-66 94 SPH-1251

59 45 MH-71 95 SPH-1252

200 52 MH-72 96 SPH-1253

60 5,4 MH-75 97 SPH-1254

200 3 MH-76 98 SPH-1255

200 200 MH-81 99 SPH-1256

200 14 MH-83 93 SPH-1259

140 80 HM 60 29 SPH-1262

54,5 36 MR 14 42 SPH-1263

200 200 Ap 74 1 SPH-1264

50 200 HM 58 33 SPH-1266

30 200 CB 75 59 SPH-1267

30 200 CB 73 25 SPH-1268

44 200 CB 78 55 SPH-1269

2,6 10 CB 85 57 SPH-1270

2,5 7 CB 86 58 SPH-1271

15 4 CB 87 69 SPH-1272

6,7 30 CB 81 60 SPH-1273

21 3,4 CB 99, BK 10 145 SPH-1276

42 40 CB 89 68 SPH-1277

33 7,3 HM 57 41 SPH-1278

100 32 HM 60 32 SPH-1280

0,5 0,24 CB 98 48 SPH-1282

4 0,54 CB 100, BK 11 49 SPH-1283

93 100 DD 9 76 SPH-1284

8 90 DD 10 75 SPH-1286

0,3 15 BK-32-1-3, AH B 72 SPH-1287

18,5 63 HM 109 56 SPH-1288

6,3 60 HM 112, DD 13 146 SPH-1289

0,7 1,2 HM 117 61 SPH-1290

1,2 100 MH 123-3, AH 11 110 SPH-1291

0,8 200 MH 123-3, TT 33 110b SPH-1292

40 100 CB 112 53 SPH-1293

4,2 25 MH 122-3, Pi-4 114 SPH-1295

15 32 BM 1 63 SPH-1296

46 200 CB 147, DD 16 51 SPH-1298

200 70 MH-117 106 SPH-1302

23 200 HM 203 147 SPH-1309

200 200 MT 176 128d SPH-1310

5,3 200 MT 141 83 SPH-1311

1,3 2,1 BM 4 65 SPH-1312

3 2,4 DD 24 73 SPH-1314

8,4 2,4 DD 18 64 SPH-1315

2,8 5 70 SPH-1317

80 200 PI 12 111 SPH-1318

200 200 PI 14 112 SPH-1319

200 200 PI 19 23 SPH-1320

83 30 PI 21 116 SPH-1326

8,4 2,6 CB 171 54 SPH-1327

24 3 WO 2 50 SPH-1328

7,2 200 CB 161 52 SPH-1329

2,9 0,85 DD 26 67 SPH-1330

64 67 RMA 15 78 SPH-1331

50 200 MH 142 119 SPH-1332

200 200 MH 145 120 SPH-1333

9 23 RMA 14, DD 7 79 SPH-1335

0,02 0,8 CB 177, BK 6 6-Stufe 3 SPJ-1339

0,3 1,5 HM 264-1 149 SPH-1340

32 30 HM 265-1 150 SPH-1345

200 200 MH 143 1.19

SPH 1346

200 200 MH 146 121

SPH-1357

0,022 0,8 MF 8 151 SPH-1359

0,0052 0,24 MF 19 7-Stufe3 SPH-1362

3 200 MF-3, CK-21-3 181 SPH-1363

3,6 20 MF-17, CK-24-2 180 SPH-1369

0,022 1,5 MT 273 3 SPH-1371

0,36 BK-32-2, BK-32-1-3 170 SPH-1372

0,022 UJ-1682-2 4 SPH-1373

0,043 UJ-1685 5 SPH-1374

0,027 UJ-1686 3 SPH-1375

0,023 UJ-1683 7 SPH-1376

0,02 UJ-1684 6 SPH-1377

0,024 BK-34-2 155 SPH-1490

MB-8 171 SPH-1491

MB-1 172 SPH-1492

MB-7 173 SPH-1493

MB-10 174 SPH-1494

MB-15 175 SPH-1515

ML-7 157 SPH-1521

176 SPH-1522

CK-52-6 158 SPH-1523

CK-58-2 159 SPH-1524

CK-65-1 160 SPH-1525

CK-63 161 SPH-1526

CK-63 162 SPH-1528

CK-49-1-IPP-3-1 163 SPH-1529

CK-59-AcPP-3-1 164 SPH-1530

CK-59-ISS-4-1 165 SPH-1531

CK-59-IPP-2-1 166 SPH-1532

CK-59-MSS-5-1 167 SPH-1534

CK-9-2 182 SPH-1535

CK-10 183 SPH-1536

CK-32 184 SPH-1537

CK-17 185 SPH-1538

CK-17-1 186 SPH-1539

CK-36 187 SPH-1540

CK-41 188 SPH-1541

CK-48 189 SPH-1542

CK-43-5 190 SPH Number Structure IC50 AChE μM IC50 BChE μM SPH-NummerStruktur IC50 AChE μM IC50 BChE μM SPH-1193

1,5 0,8

Within the scope of the invention, i.a., the compound(6R)-3-methoxy-5,6,9,10,11,12-hexahydro-4a[H1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(norgalanthamine), specifically racemic norgalanthamine, (−)norgalanthamine and (+) norgalanthamine, is especially to be considered.Both racemic norgalanthamine and its (+)- and (−)-isomers can be used inpharmaceutical agents for treatment of the diseases mentioned aboveunder a) to m) as active ingredients per se or in combination with otheractive ingredients.

The compounds according to the invention can be synthesized with properuse of the process and modes of operation for the production ofgalanthamine and galanthamine derivatives described in WO 96/12692 andWO 97/40049.

An addition to the above-mentioned synthesis methods, some of thecompounds according to the invention can be produced with use of thecombinatory (or parallel) synthesis technology. With this synthesismethod, the skeleton of interest (or nuclear molecule) is immobilized ina solid phase (e.g., glass pellets, polymer pellets or another inertvehicle), which facilitates the separation of excess reactants from amodified skeleton. The solid phase that is used in each case depends onthe concentration capacity, the reactants that are used and the reactionsolvents. In particular, polymer pellets, such as, for example,Merriefield resin, Wang resin or TentaGel (Rapp) resin, are considered.

The immobilization of the skeleton is carried out by a functional groupthat can be recovered in the last step of the synthesis under suitablereaction conditions. The last step consists in the cleavage of thedesired product from the solid phase. The selection of the linker unit,which couples the basic molecule to the solid phase, depends on thecombination and/or the series of reactants and the reaction conditionsthat are necessary to obtain maximum yields and/or purity. Moreover,with different linkers, the products can be cleaved off from the samesolid phase under different conditions. This technology allows a quicksynthesis including automated syntheses of compounds according to theinvention.

Relative to the combinatory and/or parallel synthesis, reference is madeto the bibliographic references below, in which general processdescriptions are included:

-   1) Abelson, J. N., Combinatorial Chemistry. Academic Press, San    Diego (1996).-   2) Epton, R., Innovation and Perspectives in Solid Phase Synthesis    and Combinatorial Libraries, Mayflower Scientific Limited,    Birmingham (1996).-   3) Wilson, S. R. and Czarnik, A. W., Combinatorial Chemistry.    Synthesis and Applications. John Wiley & Sons, Inc., New York    (1997).-   4) Gordon, E. M. and Kerwin, J. F. J., Combinatorial Chemistry and    Molecular Diversity in Drug Discovery. John Wiley and Sons, Inc.,    New York (1998).-   5) Thompson, L. A., Ellman, J. A. Chem. Rev. 96, 555 (1996).-   6) Special Issue on Combinatorial Chemistry, cf., Acc. Chem. Res.,    29, 111 (1996).-   7) Fruchtel, J. S.; Jung, G. Angew. Chem. [Applied Chemistry] Int.    Ed. Engl. 35, 17 (1996).-   8) Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.;    Boger, D. L. J. Am. Chem. Soc., 118, 2567 (1996).-   9) For additional information regarding this quickly developing    field, see: A Dynamic Database of References in Molecular Diversity    at http://www.5z.com.-   10) Bayer, E.; Angew Chem. Int. Ed., 30, 113-129 (1991).-   11) Mayer, J. P.; Zhang, J.; Bjergarde, K.; Lentz, D. M.;    Gaudino, J. J.; Tetrahedron Letters, 37, 8081 (1996).-   12) Bayer, E.; Angew. Chem. Int. Ed., 30, 113-129 (1991).-   13) DE 19745628 A1.

In the example of a norgalanthamine skeleton (G₁=G₂ G₃=methylene; W═NH)or “homogalanthamine (G₁=G₂=G₃=methylene; W═CH—NH₂), a bond between themolecule and the solid phase can be obtained either via a carbon center(C-linked), a nitrogen center (N-linked) or an oxygen center (O-linked).The linkage points depend on the type of structural modificationdesired. In the reaction diagrams mentioned below by way of example,various transformations of skeletons linked by linkers to various solidphases are depicted.

O-Linker Transformations of Skeletons of the Norganlanthamine Type andthe “Homogalanthamine” Type

N-Linker Transformations of a Molecule Skeleton of the NorgalanthamineType

C-Linker Transformations of a Skeleton of the Norgalanthamine Type

C-Linker Transformations of the “Homogalanthamine Skeleton”

The compounds according to the invention, as well as pharmaceuticallyacceptable acid addition salts thereof can be used as active ingredientsin pharmaceutical agents, for example for treating diseases withapoptotic components.

Neurodegenerative diseases of the human nervous system belong to thesyndromes for which few or no causal treatment methods are nowavailable. Neurological diseases of this type with chronic course areprimarily defined as follows:

-   -   Primary degenerative dementias (primarily Alzheimer's disease),    -   Cerebral and spinal paralysis (amyotrophic lateral sclerosis,        multiple sclerosis),    -   Centrally induced motor disturbances (Parkinson's disease and        Huntington's disease) and    -   Diseases of the epileptic group.

Neurodegeneration, however, also plays a role in the immediate wake ofacute neurological cases, among which primarily the following can bementioned:

-   -   Ischemic stroke (obstruction of an artery supplying the brain),    -   hemorrhagic stroke (internal cerebral hemorrhage),    -   cranio-cerebral trauma, and    -   brain damage after cardiac failure or respiratory arrest        (hypoxia/anoxia).

The compounds of the invention as well as pharmaceutically acceptableacid addition salts thereof can use active ingredients of pharmaceuticalagents for treatment of neurodegenerative processes, whereby the primaryaim is not to bring about an improvement of the acute symptoms and signsbut rather a slowing and modification of the associated processes.

Within the framework of diabetes mellitus type II, there is increasingevidence of a role of amyloid fragments in the cell degeneration of theinsulin-producing Langerhans' islet cells. The cell degeneration can beaggravated by a non-controlled calcium inflow. ^(1,2,3)

The compounds according to the invention as well as pharmaceuticallyacceptable acid addition salts thereof can be used as active ingredientsin pharmaceutical agents, for example for treating degenerative diseasesof the islet cells (such as, e.g., diabetes mellitus type II).

The compounds of the invention can be used as active ingredients inpharmaceutical agents that can be used as follows:

-   -   a) for treatment of Alzheimer's disease,    -   b) for treatment of Parkinson's disease,    -   c) for treatment of Huntington's disease (chorea),    -   d) for treatment of multiple sclerosis,    -   e) for treatment of amyotrophic lateral sclerosis,    -   f) for treatment of epilepsy,    -   g) for treatment of the sequelae of stroke,    -   h) for treatment of the sequelae of cranio-cerebral trauma,    -   i) for treatment and prophylaxis of the sequelae of diffuse        oxygen and nutrient deficiency in the brain, as they are        observed after hypoxia, anoxia, asphyxia, cardiac arrest,        poisonings, as well as in the case of complications in difficult        deliveries of infants or in the case of anesthesia,    -   j) especially also for prophylactic treatment of apoptotic        degeneration in neurons that were or are damaged by local        radiotherapy or chemotherapy of brain tumors, and    -   k) for treatment of bacterial meningitis and    -   l) for treatment of diseases with apoptotic components,        especially in the wake of an amyloid-associated cell        degeneration,    -   m) for treatment of diabetes mellitus, especially if it is        accompanied by amyloid degeneration of islet cells.

The compounds according to the invention or their pharmaceuticallyacceptable acid addition salts, e.g., hydrobromide, hydrochloride,methyl sulfate, methiodide, tartrate, fumarate, oxalate, etc. (see tablebelow) can be administered to patients orally, rectally or bysubcutaneous, intramuscular, intravenous or intrathecal injection orinfusion, or intracerebroventricularly, e.g., using an implantedcontainer. English Acid Salt Sulfamic Sulfamic acid — Amidosulfonic acidAmidosulfonate 1,2- 1,2- 1,2- ethanedisulfonic ethanedisulfonicethanedisulfonate acid 2-ethylsuccinic 1,2-ethylsuccinic2-ethylsuccinate acid 2-hydroxyethanesulfonic = isethionic2-hydroxyethanesulfonic 2-hydroxyethanesulfonate acid 3-hydroxynaphthoic3-hydroxynaphthoic 3-hydroxynaphthoate acid acetic acetic acid acetatebenzoic benzoic acid benzoate benzenesulfonic benzenesulfonicbenzenesulfonate acid calcium calcium dihydrogen calciumdihydrogenedetic ethylenediamine ethylenediamine tetraacetic acidtetraacetate camphorsulfonic camphorsulfonic camphorsulfonate acidcarbonic carbonic acid carbonate citric citric acid citratedodecylsulfonic dodecylsulfonic dodecylsulfonate acid ethanesulfonicethanesulfonic acid ethanesulfonate edetic ethylenediamineethylenediamine tetraacetic acid tetraacetate fumaric fumaric acidfumarate glubionic glubionic acid glubionate glucoheptonic glucoheptonicacid glucoheptonate gluconic gluconic acid gluconate glutamic glutamicacid glutamate hexylresorcinic hexylresorcylic hexylresorcylate acid HBrhydrobromic acid hydrobromide HCl hydrochloric acid hydrochloridebicarbonic carbonic acid bicarbonate bitartaric tartaric acid hydrogentartrate hydriodic hydriodic acid hydriodide lactic lactic acid lactatelactobionic lactobionic acid lactobionate laevulinic laevulinic acidlaevulinate estolic laurylsulfuric acid laurylsulfate (laurylsulfuric)LIPOIC-(ALPHA) ACID lipoic acid liponate malic malic acid malate maleicmaleic acid maleinate malonic malonic acid malonate methanesulfonicmethanesulfonic methanesulfonate acid naphthalenesulfonic napththalene-naphthalene sulfonic acid sulfonate nitric nitric acid nitratepantothenic pantothenic acid pantothenate phosphoric phosphoric acidphosphate polygalacturonic polygalacturonic polygalacturonate acidpectic acid propionic propionic acid propionate salicylic salicylic acidsalicylate succinic succinic acid succinate sulfuric sulfuric acidsulfate tartaric tartaric acid tartrate

Typical dosage rates in administration of these active ingredientsdepend on the nature of the compound that is used and in intravenousadministration are in the range of 0.01 to 2.0 mg per day and perkilogram of body weight based on the physical condition and othermedications of the patient.

The following specific formulations can be used:

Tablets and capsules that contain 0.5 to 50 mg

Solution for parenteral administration that contains 0.1 to 30 mg ofactive ingredient/ml

Liquid formulations for oral administration at a concentration of 0.1 to15 mg/ml

Liquid formulations for intracerebroventricular administration, at aconcentration of 1 or 5 mg of active ingredient/ml.

The compounds according to the invention can also be a transdermalsystem, in which 0.1 to 10 mg/day is released.

A transdermal dosage system consists of a storage layer that contains0.1 to 30 mg of the active substance as a free base or salt in any casetogether with a penetration accelerator, e.g., dimethyl sulfoxide, or acarboxylic acid, e.g., octanoic acid, and a realistic-lookingpolyacrylate, e.g., hexylacrylate/vinyl acetate/acrylic acid copolymerincluding softeners, e.g., isopropylmyristat. As a covering, an activeingredient-impermeable outside layer, e.g., a metal-coated, siliconizedpolyethylene patch with a thickness of, for example, 0.35 mm, is used.To produce an adhesive layer, e.g., adimethylaminomethacrylate/methacrylate copolymer in an organic solventis used.

The invention also relates to pharmaceutical compositions that in apharmaceutically acceptable adjuvant contains a therapeuticallyeffective amount of at least one of the compounds that are proposedaccording to the invention.

The invention also extends to the use of these compounds for theproduction of pharmaceutical agents and processes for the production ofsuch compounds.

In particular, the compounds according to the invention, which in manycases show a cholinesterase-inhibiting action, are suitable astherapeutic and/or prophylactic active ingredients for senile dementia,Alzheimer's disease, etc. The compounds that are proposed according tothe invention are new tetracyclic, condensed, heterocyclic compounds.

In addition to the therapeutic and/or prophylactic properties, thecompounds and compositions according to the invention can also be usedin the diagnosis of disease conditions of the above-mentioned type.

LITERATURE

-   1) Kawahara, M.; Kuroda, Y.; Arispe, N.; Rojas, E.; “Alzheimer's    Beta-Amyloid, Human Islet Amylin, and Prion Protein Fragment Evoke    Intracellular Free Calcium Elevations by a Common Mechanism in a    Hypothalamic BnRH Neuronal Cell Line.” J Biol Chem 2000 May 12; 275    (19): 14077-83-   2) Ma, Z.: Westermark, P.; Westermark, G T; “Amyloid in Human Islets    of Langerhans: Immunologic Evidence that Islet Amyloid Polypeptide    is Modified in Amyloidogenesis.” Pancreas 2000 August; 21(2): 212-8-   3) Rhoades, E.; Agarwal, J.; Gafni, A.; “Aggregation of an    Amyloidogenic Fragment of Human Islet Amyloid Polypeptide.” Biotin    Biophys Acta 2000 Feb. 9; 1476(2): 230-8

Below, operating instructions and examples for the production ofcompounds according to the invention are indicated.

General Remarks

“Concentration” refers to the removal of solvents under reduced pressureby means of a rotary evaporator.

“MPLC” refers to a chromatographic purification on silica gel 20-60 μmwith use of Büchi chromatography columns, a Shimadzu LC-8A pump and aShimadzu 6AV UV detector.

EXAMPLE 1 Step 1: 4-Bromo-2-methoxy-5-(2-nitroethenyl)-phenol

40.0 g (173 mmol) of 2-bromo-5-hydroxy-4-methoxybenzaldehyde and 13.3 g(173 mmol) of ammonium acetate are refluxed in 400 ml of nitromethanefor 15 minutes. The reaction mixture is evaporated to the dry state, theresidue is digested in about 70 ml of methanol and then suctioned off.To obtain a second fraction of the product, the methanol solution isconcentrated by evaporation to about 30 ml and then poured onto 500 mlof water. The precipitated solid is filtered off by suction, washed withabout 100 ml of water and dried together with the first fraction at 50°C./50 mbar, by which a total of 43.6 g (92% of theory) of yellowcrystals is obtained on 4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol witha melting point of 152-154° C.

TLC: CH₂Cl₂: MeOH=9:1

¹H-NMR (CDCl₃; δ (ppm): 3.85 (s, 3H, OCH₃); 7.30 (s, 1H, H-6); 7.38 (s,1H, H-3); 8.03 (d, ³J_(HH)=13.41 Hz, 1H, ArCH═); 8.16 (d, ³J_(HH)=13.41Hz, 1H, ═CHNO₂)

¹³C-NMR (CDCl₃; δ (ppm) 56.3 (q, OCH₃); 114.7 (d, C-6); 116.1 (d, C-3);116.6 (s, C-2); 121.4 (s, C-1); 136.8 (d, ArCH═); 137.6 (d, ═CHNO₂);146.5 (s, C-5) 152.2 (s, C-4)

Step 2: 4-Bromo-2-methoxy-5-(2-aminoethyl)-phenol

Method A:

7.2 g (74 mmol) of concentrated sulfuric acid is added in drops at 0° C.under nitrogen atmosphere to 168 ml (148 mmol) of a 0.88N lithiumaluminum hydride solution in diethyl ether. 10.0 g (36.5 mmol) of4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol is partially dissolved inone liter of absolute diethyl ether in boiling heat, and then thesupernatant solution is added with a transfer needle and dry nitrogen tothe aluminum hydride solution at room temperature. After the addition iscompleted, 700 ml of diethyl ether from the reaction mixture isdistilled in undissolved 4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol inthe receiving flask. By heating to reflux, a saturated solution isproduced that is fed to the reaction mixture as above. This process isrepeated (three to four times) until the addition of4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol is completed. Then, it ishydrolyzed with water at 0° C., and the ethereal phase is extractedtwice with 300 ml each of 4N hydrochloric acid. The acid solution ismixed with 22.2 g (148 mmol) of L-(+)-tartaric acid, made basic withconcentrated aqueous ammonia and exhaustively extracted with chloroform.The combined organic phases are washed with saturated aqueous sodiumchloride solution, dried (Na₂SO₄), filtered and concentrated byevaporation, by which 2.20 g (24% of theory) of colorless crystals isobtained on 4-bromo-2-methoxy-5-(2-aminoethyl)-phenyl with a meltingpoint of 170-172° C.

Method B:

A solution of 18.0 g (65.7 mmol) of4-bromo-2-methoxy-5-(2-nitroethenyl)-phenol in 200 ml of absolutetetrahydrofuran is added in drops over the course of 2 hours undernitrogen to a reflux-heated solution of 15.0 g (394.2 mmol) of lithiumaluminum hydride in 1 l of absolute tetrahydrofuran. Then, while beingcooled with ice, the reaction mixture is hydrolyzed with about 20 ml ofwater and evaporated to the dry state. The residue is taken up in 500 mlof 2N hydrochloric acid and washed with 500 ml of ethyl acetate. Thewashing phase is shaken back with 200 ml of 2N hydrochloric acid, thecombined aqueous phases are mixed with 70 g (467 mmol) of L-(+)-tartaricacid, made basic with concentrated aqueous ammonia and extracted threetimes with 800 ml of chloroform each. The combined organic phases aredried on sodium sulfate, filtered and concentrated by evaporation, bywhich 9.92 g (61% of theory) of colorless crystals is obtained on4-bromo-2-methoxy-5-(2-aminoethyl)-phenol with a melting point of170-172° C.

Step 3:4-Bromo-5-{N-[(4-hydroxyphenyl)methyl]-2-aminoethyl}-2-methoxyphenol

6.4 g (26.0 mmol) of 4-bromo-2-methoxy-5-(2-aminoethyl)-phenol and 3.2 g(26.0 mmol) of p-hydroxy-benzaldehyde are refluxed for 2 hours in 150 mlof absolute ethanol. Then, while being cooled with ice, 5.0 g (132.0mmol) of sodium borohydride is added and refluxed for another half hour,the excess sodium borohydride is destroyed by adding approximately 1 mlof glacial acetic acid as well as 50 ml of water while being cooled withice, and the solution is concentrated by evaporation. The residue isacidified with 2N hydrochloric acid and washed with 50 ml of chloroform.During hydrolysis, optionally larger solid fragments can form, whichmust be ground before extraction since they include large amounts ofproduct. The washing phase is shaken back with 30 ml of 2N hydrochloricacid, the combined aqueous phases are made basic with concentratedaqueous ammonia and extracted three times with 80 ml each of ethylacetate. The organic phases are combined, dried on sodium sulfate,filtered and concentrated by evaporation, by which 8.9 g (97% of theory)of colorless crystals is obtained on4-bromo-5-{N-[(4-hydroxyphenyl)methyl]-2-aminoethyl}-2-methoxyphenolwith a melting point of 69-72° C.

TLC: CHCl₃:MeOH=9:1+2% NH₃

¹H-NMR (DMSO; δ (ppm)): 2.55-2.78 (m, 4H, ArCH ₂CH ₂NH); 3.58 (s, 2H,NHCH ₂Ph); 3.73 (s, 3H, OCH₃); 6.60-6.76, 7.02-7.14 (2*m, 6H, 2* Ph)

¹³C-NMR (DMSO; δ (ppm)): 35.2 (t, ArCH₂); 48.7 (t, CH₂ CH₂NH); 52.2 (t,NHCH₂Ph); 55.9 (q, OCH₃); 111.3 (s, C-4); 114.8 (d, C-3′); 115.9 (d,C-6); 117.3 (d, C-3); 129.1 (d, C-2′); 130.7 (s, C-5); 131.4 (s, C-1′);146.0 (s, C-2); 146.8 (s, C-1); 156.0 (s, C-4′)

Step 4:N-[2-(2-Bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N-[(4-hydroxyphenyl)methyl]formamide

8.5 g (24.1 mmol) of4-bromo-5-{N-[(4-hydroxyphenyl)methyl]-2-aminoethyl}-2-methoxyphenol and10 ml (123.8 mmol) of ethyl formate are refluxed with 2.5 ml of formicacid, 10 ml of N,N-dimethylformamide and a spatula-tip full ofdimethylaminopyridine in 150 ml of absolute dioxane for 24 hours. Towardthe end of the reaction, the initially white suspension turns clear, andthe mixture is mixed with 50 ml of water. The dioxane is distilled off,the white precipitate that is produced is filtered off by suction andwashed with water, by which the first fraction product is obtained. Thefiltrate is extracted three times with 50 ml each of ethyl acetate, thecombined organic phases are dried on sodium sulfate, filtered andconcentrated by evaporation. By subsequent column chromatography (50 gof silica gel, mobile solvent: CHCl₃:MeOH=97:3), another fraction isobtained. Both fractions are dried at 50° C./50 mbar until a constantweight is reached, by which a total of 6.6 g (72% of theory) ofcolorless crystals is obtained onN-[2-(2-bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N-[(4-hydroxyphenyl)methyl]-formamidewith a melting point of 104-106° C.

TLC: CHCl₃:MeOH=9:1

¹H-NMR (DMSO; δ (ppm)): 2.56-2.78 (m, 2H, ArCH₂); 3.43-3.53 (m, 2H,CH₂N); 3.72 (s, 3H, OCH₃); 4.14 (dd, 2H, NCH₂Ph); 6.67-6.80, 7.00-7.11(2*m, 6H, Ar, Ph); 9.30, 9.48 (2* s, 1H, CHO)

¹³C-NMR (DMSO; δ (ppm)): 32.6, 34.2 (2* t, ArCH₂); 41.5, 44.3 (2* t,CH₂N); 46.1, 50.4 (2* t, NCH₂Ph); 56.1 (q, OCH₃); 111.4, 111.6 (2* s,C-4); 115.1, 115.2 (2* d, C-6); 115.6, 115.7 (2* d, C-3′) 117.7, 118.0(2* d, C-3); 126.8, 127.0 (2* s, C-5); 129.4 (d, C-2′); 130.0 (s, C-1′);146.5, 146.6 (2* s, C-2); 147.5, 147.6 (2* s, C-1); 157.1, 157.5 (2* s,C-4′); 162.7, 163.0 (2* d, CHO)

Step 5:(4aα,8aα)-4a,5,9,10,11-Hexahydro-1-bromo-3-methoxy-6-oxo-6H-benzofuro[3a,3,2-ef]-[3]benzazepine-10-carboxyaldedyde

A mixture of 13 g (39.5 mmol) of potassium hexacyanoferrate (III), 300ml of chloroform and 50 ml of aqueous 10% potassium carbonate solutionis heated to 60° C., mixed with 3 g (7.9 mmol) ofN-[2-(2-bromo-5-hydroxy-4-methoxyphenyl)ethyl]-N-[(4-hydroyphenylyl)methyl]-formamidewhile being stirred vigorously and then mechanically stirred vigorouslyfor another 10 minutes. Then, the brown solid that is produced isfiltered off on Hyflo, rewashed three times with 30 ml each ofchloroform and pressed out solid. The filtrate is then washed with about150 ml of water, the washing phase is shaken back with 150 ml ofchloroform, the combined organic phases are dried on magnesium sulfate,filtered and concentrated by evaporation. By purification on columnchromatography (15 g of silica gel, mobile solvent: CHCl₃:MeOH=97:3),580 mg (19% of theory) of colorless crystals with a melting point of218-220° C. is obtained.

TLC: CHCl₃:MeOH=9:1

¹H-NMR (CDCl₃; δ (ppm)): 2.58-4.27 (m, 8H, H-5/5′/9/9′/11/11′/12/12′);3.80 (s, 3H, OCH₃); 4.85 (dd, 1H, H-4a); 6.09 (dd, 1H, H-8); 6.53 (dd,1H, H-7); 7.01 (s, 1H, H-2); 8.10, 8.30 (2* s, 1H, CHO_(Conf. A/B))

¹³C-NMR (CDCl₃; δ (ppm)): 33.4, 35.3 (2*t, C-9_(Conf. A/B)); 37.2, 37.4(2*t, C-5_(Conf. A/B)); 43.7 (t, C-11); 48.7, 49.0 (2*t,C-12_(Conf. A/B)); 50.9, 51.4 (2*s, C-8a_(Conf. A/B)) 56.2 (q, OCH₃);83.8, 84.3 (2*s, C-4a_(Conf. A/B)); 115.3, 115.7 (2*s, C-1_(Conf. A/B));116.8, 117.0 (2*d, C-8_(Conf. A/B)); 127.6, 128.9 (2*s,C-12a_(Conf. A/B)); 128.0, 128.8 (2*d, C-7_(Conf. A/B)) 129.8, 130.8(2*s, C-12b_(Conf. A/B)); 141.5, 141.7 (2*d, C-2 Conf. A/B); 143.8,144.0 (2*s, C-3a_(Conf. A/B)); 146.8 (s, C-3); 161.7, 162.3 (2*d, CHO);193.0, 193.4 (2*s, C-6)

C₁₇H₁₆BrNO₄ (JOS 1526) 378.23 g/mol Cld.: C 53.99 H 4.26 N 3.70 Fnd.: C53.70 H 4.47 N 3.41

Step 6:(4aα,8aα-4a,5,9,10,11-Hexahydro-1-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef]-[3]benzazepin-6-ol

4 ml (4.00 mmol) of 1N L-selectride solution is added in drops at −12°C. under nitrogen to a solution of 500 mg (1.32 mmol) of(4aá,8aá)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6-oxo-6H-benzofuro[3a,3,2-ef][3]benzazepine-10-carboxaldehydein 12 ml of absolute tetrahydrofuran, and the reaction mixture is thenstirred for one hour at −10° C. Then, it is hydrolyzed with 3 ml ofmethanol, the solution is evaporated to the dry state, taken up in 50 mlof 2N hydrochloric acid and stirred vigorously for another hour. Theaqueous solution is washed with 50 ml of ethyl acetate, the washingphase is shaken back with 20 ml of 2N hydrochloric acid, the combinedaqueous phases are made basic with concentrated aqueous ammonia andextracted three times with 50 ml each of ethyl acetate. The combinedorganic phases are dried on magnesium sulfate, filtered and concentratedby evaporation, by which 380 mg (82% of theory) of light yellow crystalsis obtained on(4aα,8aα)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][3][benzazepin-6-olwith a melting point of 132-136° C.

TLC: CHCl₃:MeOH=9:1

¹H-NMR (CDCl₃; δ (ppm)) 1.87 (ddd, 1H, H-5′); 2.62 (ddd, 1H, H-5′); 2.68(ddd, 1H, H-11); 2.78 (d, 1H, H-9, ²J_(9/9′)=12.6 Hz); 2.85 (ddd, 1H,H-11′); 2.98 (d, 1H, H-9′, ²J_(9/9′)=12.6 Hz); 3.30 (ddd, 1H, H-12);3.37 (ddd, 1H, H-12′); 3.80 (s, 3H, OCH₃); 4.08 (ddd, 1H, H-6); 4.50(dd, 1H, H-4a); 6.08 (dd, 1H, H-8, ³J_(7/8)=10.2 Hz); 6.15 (d, 1H, H-7,³J_(7/8)=10.2 Hz); 6.96 (s, 1H, H-2)

¹³C-NMR (CDCl₃; δ (ppm)): 30.2 (t, C-5); 36.7 (t, C-9); 49.7 (t, C-11);51.6 (s, C-8a); 56.0 (q, OCH₃); 57.3 (t, C-12); 62.0 (d, C-6); 85.5 (d,C-4a); 114.9 (s, C-1); 115.7 (d, C-8); 127.3 (d, C-2); 127.7 (d, C-7);130.5 (s, C-12a); 134.2 (s, C-12b); 143.5 (s, C-3a); 145.4 (s, C-3)

Step 7:(4aα,8aα)-4a,5,9,10,11-Hexahydro-1-bromo-3-methoxy-10-methyl-6H-benzofuro[3a,3,2-ef]-[3]benzazepin-6-ol

In succession, 1 ml of 35% aqueous formaldehyde solution and, inportions, 165 mg (2.63 mmol) of sodium cyanoborohydride are added whilebeing stirred vigorously to a solution of 370 mg (1.05 mmol) of(4aα,8aα)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-olin 12 ml of acetonitrile, and the reaction mixture is stirred vigorouslyat room temperature for one hour. The solution is then acidified with 2Nhydrochloric acid, washed with 15 ml of dichloromethane, and the washingphase is shaken back with 15 ml of 2N hydrochloric acid. The combinedorganic phases are made basic with concentrated aqueous ammonia andextracted three times with 30 ml of dichloromethane each. The combinedorganic phases are dried on magnesium sulfate, filtered and concentratedby evaporation, by which 355 mg (92% of theory) of yellow crystals isobtained on(4aα,8aα)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-10-methyl-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-olwith a melting point of 158-161° C.

TLC: CHCl₃:MeOH=9:1

¹H-NMR (CDCl₃; δ (ppm)): 1.91-2.04 (m, 1H, H-5); 2.27-2.48 (m, 2H,H-5′/11); 2.41 (s, 3H, NCH₃); 2.60-2.81 (m, 2H, H-9/11′); 2.92-3.16 (m,2H, 9′/12); 3.34 (dd, ³J_(11/12′)=6.37 Hz, ²J_(12/12′), =16.48 Hz, 1H,H-12′); 4.13-4.25 (m, 1H, H-6); 4.58 (b, 1H, H-4a); 6.02 (dd,³J_(7/8)=10.17 Hz, ⁴J_(6/8)=5.08 Hz, 1H, H-8); 6.18 (d, ³J_(7/8)=10.17Hz, 1H, H-7); 6.92 (s, 1H, H-2)

Step 8:(4aα,8aα)-4a,5,9,10,11-Hexahydro-3-methoxy-10-methyl-6H-benzofuro[3a,3,2-ef]-[3]benzazepin-6-ol

A mixture that consists of 340 mg (0.93 mmol) of(4aα,8aα)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-10-methyl-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-oland 722 mg (6.51 mmol) of calcium chloride in 40 ml of 50% ethanol ismixed with 1.4 g (22.32 mmol) of freshly activated zinc powder¹ andrefluxed for 5 hours. Then, the zinc is filtered out, it is rewashedwith methanol, and the residual solution is concentrated by evaporation.The residue is taken up in 50 ml of 1N hydrochloric acid, washed with 30ml of ethyl acetate, and the washing phase is shaken back with 20 ml ofhydrochloric acid. The combined aqueous phases are made basic withconcentrated aqueous ammonia and extracted three times with 50 ml eachof ethyl acetate. The combined organic phases are dried on magnesiumsulfate, filtered and concentrated by evaporation, by which 230 mg (86%of theory) of yellow crystals is obtained on(4aα,8aα)-4a,5,9,10,11-hexahydro-3-methoxy-10-methyl-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-olwith a melting point of 152-155° C.¹Zinc powder (Aldrich Company) mixed with 2N hydrochloric acid,thoroughly mixed, filtered off and first washed neutral with distilledwater, then thoroughly rewashed with methanol

TLC: EE:EtOH=9:1 (visible by oxidation in the iodine chamber)

¹H-NMR (CDCl₃; δ (ppm)): 1.90-2.04 (m, 1H, H-5); 2.26-2.46 (m, 2H,H-11/11′); 2.42 (s, 3H, NCH₃); 2.62-2.80 (m, 3H, H-5′/9/9′); 3.01-3.12(m, 1H, H-12); 3.12-3.29 (m, 1H, H-12′); 3.83 (s, 3H, OCH₃); 4.12-4.22(m, 1H, H-6); 4.57 (b, 1H, H-4a); 6.01 (ddd, ³J_(7/8)=10.16 Hz,⁴J_(6/8)=5.18 Hz, ⁵J_(5/8)=0.95 Hz; 1H, H-8); 6.22 (dd, ³J_(7/8)=10.16Hz, ⁴J_(5/7)=1.09 Hz, 1H, H-7); 6.61 (d, ³J_(1/2)=8.21 Hz, 1H, H-2) 6.66(d, ³J_(1/2)=8.21 Hz, 1H, H-1)

¹³C-NMR (CDCl₃; δ (ppm)): 30.0 (t, C-5); 34.5 (t, C-9); 48.9 (s, C-8a);49.3 (q, NCH₃); 55.6 (q, OCH₃); 59.1 (t, C-11); 62.0 (d, C-6); 66.3 (t,C-12); 85.6 (d, C-4a); 111.1 (d, C-1); 121.5 (d, C-8); 126.5 (d, C-2);128.3 (d, C-7); 130.9 (s, C-12a); 132.7 (s, C-12b); 142.9 (s, C-3a);145.3 (s, C-3b);

EXAMPLE 2(4aα,8aα)-4a,5,9,10,11-Hexahydro-1-bromo-6-[(4-bromophenyl)methyl]-3-methoxy-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol

A mixture of 23 mg (0.068 mmol) of(4aα,8aα)-4a,5,9,10,11-hexahydro-1-bromo-3-methoxy-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-ol,19 mg (0.136 mmol) of potassium carbonate and 12 mg (0.082 mol) ofsodium iodide is mixed in 20 ml of absolute acetone with 21 mg (0.082mmol) of 4-bromobenzyl bromide and refluxed. After one hour, thereaction mixture is concentrated by evaporation, the residue is taken upin 10 ml of 2N hydrochloric acid, washed with ethyl acetate, made basicwith concentrated aqueous ammonia and extracted three times with 5 mleach of ethyl acetate. The combined organic phases are washed once withsaturated aqueous sodium chloride solution, dried (Na₂SO₄, activatedcarbon), filtered and concentrated by evaporation. Further purificationis carried out via flash chromatography (15 g of silica gel; mobilesolvent: CHCl₃═CHCl₃:MeOH=95:5), by which 10 mg (29% of theory) of oilysubstance on(4aα,8aα)-4a,5,9,10,11-hexahydro-1-bromo-6-[(4-bromophenyl)methyl]-3-methoxy-6H-benzofuro[3a,3,2-ef][3]benzazepin-6-olis obtained.

TLC: CHCl₃:MeOH=9:1

¹H-NMR (CDCl₃; δ (ppm)): 1.78 (ddd, 1H, H-5); 1.98-2.31 (m, 4H,H-5′/9/11/11′); 2.70 (ddd, 1H, H-9′); 3.57 (ddd, 1H, H-12); 3.82 (s, 3H,OCH₃); 3.86 (ddd, 1H, H-12′); 4.15 (b, 1H, H-6); 4.42 (d, 1H, NCH₂);4.65 (b, 1H, H-4a); 5.00 (d, 1H, NCH₂′); 5.91 (d, 1H, H-7); 6.06 (dd,1H, H-8); 6.92 (s, 1H, H-2); 7.28 (d, 2H, Ph-2/6); 7.43 (d, 2H, Ph-3/5)

EXAMPLE 2 EXAMPLE 32-[4-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine-11-yl]butyl]-1,2-benzoisothiazol-3(2H)-one,1,1-dioxide tartrate, dihydrate (SPH-1374)

2-(6-Bromohexyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (2.33 g, 7.32mmol), produced according to Hamor, G. H.; Rubessa, F.; Farmaco Ed. Sci.1970, 25, 36-39, Norgalanthamine (2.00 g, 7.32 mmol) andN-ethyldiisopropylamine (2.84 g, 22.0 mmol) in absolute chloroform (20ml) are stirred at boiling temperature for 24 hours.

The solvent is drawn off, and the residue is purified by columnchromatography (150 g of silica gel,chloroform:methanol:ammonia:96.5:3:0.5), by which the product isobtained as a colorless foam (2.67 g, 5.23 mmol, 71.4%).

TLC: Chloroform:methanol:ammonia=89:10:1; Rf=0.5

¹H-NMR (CDCl₃): δ 8.05-7.72 (m, 4H), 6.63-6.55 (m, 2H), 6.10-5.90 (m,2H), 4.56 (b, 1H), 4.15-4.01 (m, 2H), 3.84-3.70 (m, 6H), 3.42-3.04 (m,2H), 2.71-2.35 (m, 4H), 2.10-1.72 (m, 4H) 1.65-1.40 (m, 2H);

¹³C-NMR (CDCl₃) δ 158.8 (s), 145.7 (s), 143.9 s), 137.5 (s) 134.6 (d),134.1 (d), 133.0 (s), 129.4 (s), 127.4 (d), 127.2 (s) 126.8 (d), 124.9(d), 121.8 (d), 120.7 (d), 111.0 (d), 88.5 (d), 61.9 (d), 57.5 (t), 55.7(q), 51.4 (t), 50.5 (t), 48.3 (S), 39.1 (t), 32.9 (t), 29.8 (t), 26.0(t), 24.5 (t)

The base (SPH-1369, 2.50 g, 4.90 mmol) and (+)-tartaric acid (0.80 g,5.33 mmol, 1.09 equivalents) is heated in EtOH (95%, about 10 ml) untilthe solution turns clear (about 50° C.), and this solution is addedstill hot drop by drop within 5 minutes to absolute ether (about 200 ml)that is stirred with a magnet, whereby a white precipitate is produced.After standing overnight at room temperature, the crystals that areobtained are filtered off by suction and washed with absolute ether(3×50 ml), and the product is dried in a vacuum desiccator at roomtemperature/50 mbar on calcium chloride, whereby the tartrate dihydrateis obtained in the form of a colorless powder (3.184 g, 93.3% oftheory). A sample quantity is dried at 2 mbar and 40° C. for 8 hours onphosphorus pentoxide.

C₂₇H₃₀N₂O₆S.C₄H₄O₄.2H₂O (JOS 1659) (697.7) Fnd. C 56.18 H 5.78 N 4.23Cld. a) C 55.74 H 5.81 N 4.15 b) C 55.76 H 5.79 N 4.26

EXAMPLE 42-[5-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine-11-yl]pentyl]-1,2-benzoisothiazol-3(2H)-one,1,1-dioxide (SPH-1372)

2-(5-Bromopentyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (1.66 g, 5.00mmol), norgalanthamine (1.37 g, 5.00 mmol) and N-ethyldiisopropylamine(1.94 g, 15.0 mmol) in absolute chloroform (15 ml) are stirred for 24hours at boiling temperature.

The solvent is drawn off, and the residue is purified by columnchromatography (150 g of silica gel,chloroform:methanol:ammonia:96.5:3:0.5), by which the product isobtained as a colorless foam (2.09 g, 3.99 mmol, 79.7%).

TLC: Chloroform:methanol:ammonia=89:10:1; Rf=0.5

¹H-NMR (CDCl₃): δ 8.05-7.70 (m, 4H), 6.63-6.50 (m, 2H), 6.09-5.85 (m,2H), 4.55 (b, 1H), 4.15-3.99 (m, 2H), 3.82-3.60 (m, 5H), 3.41-2.92 (m,2H), 2.70-2.32 (m, 3H), 2.09-1.70 (m, 4H), 1.58-1.23 (m, 6H);

¹³C-NMR (CDCl₃): δ 158.7 (s), 145.6 (s), 143.8 (s), 137.5 (s), 134.5(d), 134.1 (d), 133.0 (q), 129.4 (s), 127.3 (d), 127.2 (s), 126.8 (d),124.8 (d), 121.8 (d), 120.7 (d), 111.0 (d), 88.5 (d), 61.8 (d), 57.5(t), 55.7 (q), 51.4 (t), 51.0 (t), 48.2 (S), 39.1 (t), 32.8 (t), 29.8(t), 28.1 (t), 26.6 (t), 24.3 (t), 20.3 (d)

Production of Fumarate (UJ-1682)

A hot (about 50° C.) solution of the base (1.686 g, 3.21 mmol) in EtOH(95%, 10 ml) is combined with saturated fumaric acid solution (10 ml,about 0.5 M in 95% ethanol), heated at about 60° C. until a clearsolution is obtained, and this solution that is still hot is fed indrops within 5 minutes to absolute ether (about 200 ml) that is stirredwith a magnet, whereby a white precipitate is produced. After standingovernight at room temperature, the crystals that are obtained arefiltered off by suction and washed with absolute ether (3×50 ml), andthe product is dried in a vacuum desiccator at room temperature/50 mbaron calcium chloride, whereby the fumarate is obtained in the form of acolorless powder (1.394 g, 67.7% of theory). A sample quantity is driedat 2 mbar and at 40° C. for 8 hours on phosphorus pentoxide. A secondfraction is obtained from the mother liquor (=UJ-1682-1-2).

C₂₈H₃₂N₂O₆S.C₄H₄O₄.½C₄H₁₀O (JOS 1657) (677.8) Cld. C 59.54 H 6.21 N 4.21Fnd. C 59.49 H 6.18 N 4.20

EXAMPLE 52-[6-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine-11-yl]hexyl]-1,2-benzoisothiazol-3(2H)-one,1,1-dioxide fumarate (SPH-1373)

2-(6-Bromohexyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (1.50 g, 4.33mmol), produced according to Kim, Sung-Kyu; Cho, Su-Dong; Moon,Jung-Kyen; Yoon, Yong-Jin. J. Heterocycl. Chem. (1996), 33(3), 615-618,norgalanthamine (1.18 g, 4.33 mmol) and N-ethyldiisopropylamine (1.68 g,13.0 mmol) in absolute chloroform (15 ml) is stirred for 24 hours atboiling temperature. The solvent is drawn off, and the residue ispurified by column chromatography (150 g of silica gel,chloroform:methanol:ammonia:96.5:3:0.5), by which the base is obtainedas a colorless foam (1.91 g, 3.52 mmol, 81.4%).

TLC: Chloroform:methanol:ammonia=89:10:1; Rf=0.5

¹H NMR (CDCl₃) δ 8.08-7.72 (m, 4H), 6.68-6.55 (m, 2H), 6.12-5.90 (m,2H), 4.57 (b, 1H), 4.16-4.01 (m, 2H), 3.82-3.65 (m, 6H), 3.52-3.03 (m,2H), 2.71-2.28 (m, 3H), 2.10-1.71 (m, 4H), 1.55-1.25 (m, 7H);

158.8 (s), 145.7 (S), 143.9 (s), 137.6 (s), 134.6 (d), 134.2 (d), 133.1(s), 129.5 (s), 127.4 (d), 127.3 (s), 126.9 (d), 125.0 (d), 121.9 (d),120.8 (d), 111.1 (d), 88.6 (d), 62.0 (d), 57.6 (t), 55.8 (q), 51.5 (t),48.3 (t), 39.3 (t), 32.9 (t), 29.9 (t) 28.2 (t), 27.1 (t), 26.7 (t) 26.6(t)

Production of Fumarate

A clear solution that is obtained by heating the base (1.33 g, 2.47mmol) in fumaric acid solution (8 ml, saturated solution in 95% ethanol)to about 60° C. is added drop by drop within 5 minutes to absolute etherthat is stirred with a magnet, whereby a white precipitate is produced.After standing overnight at room temperature, the crystals that areobtained are filtered off by suction and washed with absolute ether(3×50 ml), and the product is dried in a vacuum desiccator at roomtemperature/50 mbar on calcium chloride, whereby the fumarate isobtained in the form of a colorless powder (1.170 g, 72% of theory). Asample quantity is dried at 2 mbar and 40° C. for 8 hours on phosphoruspentoxide.

C₂₉H₃₄N₂O₆S.C₄H₄O₄ (JOS 1658) Cld.: C 60.54, H 5.85, N 4.28 Fnd.: C60.49, H 5.97, N 4.22

EXAMPLE 6 Step 1:2-(4-Bromobutyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic acid methylester

5,6-Dimethoxy-1-oxoindane-2-carboxylic acid methyl ester (4.0 g, 16.0mmol), produced according to Fukushi, Hideto; Mabuchi, Hiroshi; Itoh,Katsumi; Terashita, Zen-ichi; Nishikawa, Kohei; Sugihara, Hirosada;Chem. Pharm. Bull. 1994, 42(3), 541-550, is added in substance at roomtemperature to a suspension of sodium hydride (0.84 g, 17.6 mmol, 50% inwhite oil, released from white oil by digestion with absolute petroleumether (3×50 ml) in absolute DMF, and the solution is stirred for 45minutes at room temperature. Then, it is mixed with 1,4-dibromobutane(24.2 g, 112.0 mmol) and stirred for 18 hours at room temperature. It isdispersed between water and ether, the aqueous phase is extractedquantitatively with ether, the combined organic phases are washed withwater (5×), saturated common salt solution (1×) and dried (sodiumsulfate/activated carbon). Excess dibromoalkane under high vacuum isseparated by bulb tube distillation (100° C./0.05 mbar) from the residuethat is obtained after concentration by evaporation, and the residuethat is obtained is recrystallized from boiling tert-butylmethyl ether(25 ml), by which the product is obtained in the form of colorlesscrystals (5.02 g, 13.0 mmol, 81.6%).

TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.15

Melting point: 92-93° C.

¹H NMR (CDCl₃): δ 7.13 (s, 1H), 6.88 (s, 1H), 3.94 (s, 3H) 3.87 (s, 3H),3.65 (s, 3H), 3.58 (d, J=18.3 Hz, 1H), 3.33 (t, J=6.7 Hz, 2H), 2.97 (d,J=17.2 Hz, 1H), 2.20-1.99 (m, 1H), 1.95-1.73 (m, 3H), 1.53-1.26 (m, 2H);

¹³C NMR (CDCl₃): δ 200.7 (s), 171.6 (s), 156.1 (s), 149.7 (s), 148.5(s), 127.7 (s), 107.1 (d), 104.8 (d), 60.6 (s), 56.2 (q), 56.0 (q), 52.6(q), 36.3 (t), 33.6 (t), 33.2 (t), 32.6 (t) 23.1 (t)

Number, chemical displacement and multiplicity of the peaks foundconfirm the postulated structure

Step 2 2-(4-Bromobutyl)-5,6-dimethoxyindan-1-one

2-(4-Bromobutyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic acid methylester (3.0 g, 7.79 mmol) is stirred in concentrated hydrochloric acid(10 ml) and acetic acid (30 ml) for 12 hours at 60° C. It is mixed withsaturated sodium carbonate solution, neutralized with sodium carbonateand extracted quantitatively with ether, the combined organic phases arewashed with saturated sodium carbonate solution (3×), water (1×),saturated common salt solution (1×), dried (sodium sulfate/activatedcarbon) and the residue that is obtained after concentration byevaporation is crystallized from tert-butylmethyl ether (10 ml). In thisway, the product is obtained in the form of colorless crystals (1.85 g,5.65 mmol, 72.5%).

TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.2

Melting point: 72-73° C.

¹H NMR (CDCl₃): δ 7.15 (s, 1H), 6.85 (s, 1H), 3.95 (s, 3H) 3.88 (s, 3H),3.40 (t, J=6.8 Hz, 1H), 3.23 (dd, J=18.0 Hz, J=8.0 Hz, 1H), 2.78-2.57(m, 2H), 2.00-1.72 (m, 3H), 1.65-1.35 (m, 3H); ¹³C NMR (CDCl₃): δ 207.1(s), 155.5 (s), 149.4 (s), 148.8 (s), 129.3 (s), 107.3 (d), 104.3 (d),56.1 (t), 56.0 (t), 47.4 (d), 33.5 (t), 32.6 (t), 32.5 (t), 30.6 (t),25.8 (t)

Step 32-(4-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine-11-yl]butyl]-5,6-dimethoxyindan-1-one

2-(4-Bromobutyl)-5,6-dimethoxyindan-1-one (1.0 g, 3.01 mmol),norgalanthamine (919 mg, 3.36 mmol) and potassium carbonate (1.26 g,9.09 mmol, anhydrous, finely ground) are stirred at boiling temperaturefor 24 hours as in absolute acetonitrile (10 ml).

The reaction mixture is filtered, the solvent is drawn off, and theresidue is purified by column chromatography (150 g of silica gel,chloroform:methanol:ammonia:96.5:3:0.5), by which the product isobtained as a colorless foam (1.21 g, 2.32 mmol, 77.6%).

TLC: Chloroform:methanol:ammonia:8.95:10:0.5, Rf=0.65

¹H-NMR (CDCl₃): δ 7.14 (s, 1H), 6.83 (s, 1H), 6.67-6.52 (m, 2H),6.12-5.90 (m, 2H), 4.57 (b, 1H), 4.02-4.18 (m, 2H), 3.93 (s, 3H), 3.87(s, 3H), 3.80 (s, 3H), 3.75 (d, J=13.7 Hz, 1H), 3.43-3.06 (m, 3H),2.75-2.35 (m, 5H), 2.11-1.83 (m, 3H), 1.59-1.29 (m, 6H);

¹³C NMR (CDCl₃): δ 207.5 (s), 155.4 (s), 149.3 (s), 148.9 (s), 145.7(s), 144.0 (s), 133.1 (s), 129.4 (s), 127.5 (d), 126.9 (d), 121.9 (d),111.1 (d), 107.3 (d), 104.2 (d), 88.6 (d), 62.0 (d), 57.7 (t), 56.1 (q),56.0 (q), 55.8 (q) 51.5 (t), 51.2 (t) 48.3 (t), 47.5 (d), 32.8 (t), 32.5(t), 31.5 (t), 29.9 (t), 27.4 (t), 25.1 (t)

EXAMPLE 7 Step 1:2-(5-Bromopentyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic acid methylester

5,6-Dimethoxy-1-oxoindane-2-carboxylic acid methyl ester (3.0 g, 12.0mmol) is added in substance at room temperature to a suspension ofsodium hydride (0.62 g, 13.2.mmol, 50% in white oil, released from whiteoil by digestion with absolute petroleum ether (3×50 ml)) in absoluteDMF, and the solution is stirred for 45 minutes at room temperature.Then, it is mixed with 1,5-dibromopentane (19.3 g, 84.0 mmol) andstirred for 18 hours at room temperature. It is dispersed between waterand ether, the aqueous phase is extracted quantitatively with ether, thecombined organic phases are washed with water (5×), saturated commonsalt solution (1×) and dried (sodium sulfate/activated carbon). Excessdibromoalkane is separated under high vacuum by bulb tube distillation(100° C./0.05 mbar) from the residue that is obtained afterconcentration by evaporation, and the residue that is obtained isrecrystallized from boiling tert-butylmethyl ether (20 ml), by which theproduct is obtained in the form of colorless crystals (3.75 g, 9.4 mmol,78.3%).

TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.15

Melting point: 108.5-100° C.

¹H NMR (CDCl₃): δ 7.15 (s, 1H), 6.89 (s, 1H), 3.96 (s, 3H) 3.89 (s, 3H),3.67 (s, 3H), 3.60 (d, J=19.1 Hz, 1H), 3.35 (t, J=7.0 Hz, 2H), 2.96 (d,J=19.1 Hz, 1H), 2.20-1.15 (m, 8H)

¹³C NMR (CDCl₃): δ 200.9 (s), 171.8 (s), 156.1 (s), 149.7 (s), 148.4(s), 127.9 (s), 107.1 (d), 104.9 (d), 60.8 (s), 56.2 (q), 56.1 (q), 52.6(q), 36.4 (t), 34.5 (t), 33.5 (t), 32.3 (t) 28.3 (t), 26.9 (d), 23.7 (t)

Step 2 2-(5-Bromopentyl)-5,6-dimethoxyindan-1-one

2-(5-Bromopentyl)-5,6-dimethoxy-1-oxoindane-2-carboxylic acid methylester (3.0 g, 7.51 mmol) is stirred in concentrated hydrochloric acid(10 ml) and acetic acid (30 ml) for 12 hours at 60° C. It is mixed withsaturated sodium carbonate solution, neutralized with sodium carbonateand extracted quantitatively with ether, the combined organic phases arewashed with saturated sodium carbonate solution (3×), water (1×),saturated common salt solution (1×), dried (sodium sulfate/activatedcarbon), and the residue that is obtained after concentration byevaporation is crystallized from tert-butylmethyl ether (10 ml). In thisway, the product is obtained in the form of colorless crystals (1.78 g,5.22 mmol, 69.5%).

TLC: Petroleum ether:ethyl acetate=3:1; Rf=0.2

Melting point: 67.5-68.5° C.

¹H NMR (CDCl₃): δ 7.15 (s, 1H), 6.85 (s, 1H), 3.95 (s, 3H), 3.89 (s,3H), 3.50 (t, J=7.0 Hz, 2H), 3.20 (dd, J=6.4 Hz, J=9.5 Hz, 1H), 2.72 (d,J=3.2 Hz, 1H), 2.60 (d, J=3.2 Hz, 1H), 2.00-1.65 (m, 3H), 1.55-1.35 (m,5H);

¹³C NMR (CDCl₃): δ 207.4 (s), 155.5 (s), 149.4 (s), 148.8 (s), 129.4(s), 107.4 (d), 104.3 (d), 56.2 (q), 56.0 (q), 47.5 (d), 44.9 (t), 32.5(t), 32.3 (t), 31.4 (t), 26.8 (t), 26.5 (t)

Step 32-[5-[(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-benzofuro[3a,3,2-e,f][2]benzazepine-11-yl]pentyl]-5,6-dimethoxyindan-1-one(SPH-1359)

2-(4-Bromopentyl)-5,6-dimethoxyindan-1-one (1.66 g, 4.86 mmol),norgalanthanamine (1.46 g, 5.35 mmol) and potassium carbonate (2.01 g,14.6 mmol, anhydrous, finely ground) are stirred for 24 hours at boilingtemperature as in absolute acetonitrile (10 ml).

The reaction mixture is filtered, the solvent is drawn off, and theresidue is purified by column chromatography (150 g of silica gel,chloroform:methanol:ammonia:96.5:3:0.5), by which the product isobtained as a colorless foam (1.84 g, 2.32 mmol, 70.9%)

TLC: Chloroform:methanol:ammonia:89.5:10:0.5, Rf=0.65

¹H NMR (CDCl₃): δ 7.11 (s, 1H), 6.82 (s, 1H), 6.63-6.54 (m, H),6.10-5.88 (m, 2H), 4.55 (b, 1H), 4.17-4.00 (m, 2H), 3.92 (s, 3H), 3.85(s, 3H), 3.78 (s, 3H), 3.73 (d, J=13.7 Hz, 1H), 3.40-3.01 (m, 3H),2.72-2.25 (m, 5H), 2.10-1.75 (m, 3H), 1.65-1.19 (m, 8H);

¹³C NMR (CDCl₃): δ 207.4 (s), 155.3 (s), 149.2 (s), 148.8 (s), 145.6(s), 143.8 (s), 133.0 (s), 129.4 (s), 129.3 (s), 127.4 (d), 126.9 (d),121.8 (d), 111.0 (d), 107.2 (d), 104.2 (d), 88.5 (d), 77.2 (d), 61.9(d), 57.6 (t), 56.0 (q), 55.9 (q), 55.7 (q), 51.4 (t), 48.2 (s), 47.5(d), 32.9 (t), 32.4 (t), 31.5 (t), 29.8 (t), 27.2 (t), 27.1 (t)

Production of Fumarate

A solution of the base (1.00, 1.8.74 mmol) in saturated fumaric acidsolution (6 ml, about 0.5 M in 95% ethanol) is heated at about 60° C.until a clear solution is obtained, and this solution that is still hotis added drop by drop within 5 minutes to absolute ether (about 150 ml)that is stirred with a magnet, whereby a white precipitate is produced.After standing overnight at room temperature, the crystals that areobtained are filtered off by suction and washed with absolute ether(3×50 ml), and the product is dried in a vacuum desiccator at roomtemperature/50 mbar on calcium chloride, whereby the fumarate isobtained in the form of a colorless powder (0.694, 57.0% of theory). Asample quantity is dried at 2 mbar and 40° C. for 8 hours on phosphoruspentoxide. A second fraction is obtained from the mother liquor.

C₃₂H₃₉NO₆.C₄H₄O₄.½H₂O (658.7) Cld. C 65.64 H 6.73 N 2.13 Fnd.: C 65.83 H6.72 N 2.10

Formulas and Table for Examples 8-79

BATCH Beispiel Nr. SPH LABCODE R1 8 3bi SPH-1218 CB 30 —C(SMe)═NCN 9 4aSPH-1229 CB 52 -pyrimidine-(2-A) 10 4b SPH-1234 CB 56-2-Cl-pyrimidine-(4-yl) 11 4c SPH-1245 CB 59 -2-NEt2-pyrimidine-(4yl) 124d SPH-1244 CB 57 -2-O(CH2)3NMe2-pyrimidine-(4-yl) 13 4e SPH-1230 CB 53-4,6-Cl-1,3,5-triazine-(2-yl) 14 4f SPH-1243 CB 584,6-di(NEt2)2-1,3,5-triazine-(2-yl) 15 4g SPH-1228 CB 43-4,6-OPh-1,3,5-triazine-(2-yl) 16 4h SPH-1233 CB 51-4,6-di(O(CH2)2NH2-1,3,5-triazine(2-yl) 17 4i SPH-1242 CB 554,6-di(O(CH2)3NMe2-1,3,5-triazine-(2-yl) 18 4j SPH-1246 MR 16 —CO—CH2Cl19 4l SPH-1214 CB 34 —CO—NHCH(Me)2 20 4m SPh-1221 CS 45 —CO—NHC(Me)3 214n SPH-1231 CB 49 —CONHEt 22 4o SPH-1222 CS 46 —CONH-cyclohexane 23 4pSPH-1215 CB 33 —CONHPh 24 4q SPH-1237 CB 47 —CONH—Ph(4-Cl) 25 4rSPH-1267 CB 73 —CO—NH—CH(Me)Ph, S-(−) 26 4s SPH-1232 CB 50—CONH-2-naphthaline 27 4t SPH-1211 CB 13 —CSNHMe 28 4u SPH-1236 CB 48—CSNHCH₂CH═CH₂ 29 4v SPH-1259 HM 59 —C(COOMe)CHCOOMe 30 SPH1196 TK 36-2—(CH2)3-(2-(4-F-phenyl)-2,5- diazabicyclo[2.2.1]heptane)-5-yl) 31 4xSPH-1219 CB 36 —CH═C(CN)2 32 4y SPH-1278 HM 60 CH═C(COOMe)2 33 4zSPH-1264 HM 58 —CHCHCOCH₂OEt 34 4ac SPH-1248 MR 7 —CH₂—COOEt 37 4afSPH-1116 Ja 6-2 —(CH2)2—NH2 40 4ai SPH-1217 CB 28 —(CH2)2—COOEt 41 4ajSPH-1277 HM 57 —(CH2)2—COOC(Me)3 42 4ak SPH-1262 MR 14 —(CH2)2—CONHCHMe243 4ab SPH-1102 TK 72/5 —CH₂—CH═CH₂ 43 4al SPH-1249 MR 13—(CH2)2—CONHCMe3 44 4am SPH-1216 CB 35 —(CH2)2—CN 45 4an SPH-1220 CB 41—(CH2)3—OH 46 4aa SPH-1103 TK 74/3 —Bn 46 4ao SPH-1235 CB 42 —(CH2)3—NH247 4ap SPH-1107 TK 94/3 —(CH2)3—N-piperidine 48 8a SPH-1280 CB 98 —Ph 498b SPH-1282 CB 100 -thiophene-2yl 50 8c SPH-1327 WO2-(N-benzoyl)-4-piperidine 51 8e SPH-1296 CB 147 —COOPh 52 8f SPH-1328 CB161 —C(═S)OPh 53 8g SPH-1292 CB 112 -Fmoc 54 8h SPH-1326 CB 171—CO—(CH2)2—CH═CH₂ 55 8i SPH-1268 CB 78 —CONH2 56 8j SPH-1287 HM 109—CSNHMe 57 8k SPH-1269 CB 85 —CO—NHCH(Me)2 58 8l SPH-1270 CB 86—CO—NHC(Me)3 59 8m SPH-1266 CB 75 —CONH—Ph(2-CF3) 60 8n SPH-1272 CB 81—C(SMe)NCN 61 8o SPH-1289 HM 117 —CH2-cyclopropane 63 8r SPH-1295 BM 1—CH₂—CN 64 8s SPH-1314 DD 18 —CH2—CO—(2-phenyl-2,5-diazabicyclo[2.2.1]heptane)-5-yl) 65 8t SPH-1311 BM4 —(CH2)2—NH2 66 8uSPH-1117 Ro21 CB 120 —(CH2)2—N-morpholine 67 8v SPH-1329 DD 26—(CH2)2-(2-phenyl-2,5- diazabicyclo[2.2.1]heptane)-5-yl) 68 8w SPH-1276CS 89 —(CH2)2—COOH 69 4ae SPH-1096 TK 81/3 —(CH2)2—OH 69 8x SPH-1271 CB87 —(CH2)2—COOC(Me)3 70 8z SPH-1315 —(CH2)3—OH 71 8aa SPH-1213 TK 96/3—(CH2)3—NMe2 72 4k SPH-1104 Ro 20 —CO(CH2)14Me 72 8ab SPH-1286 HM 113—(CH2)3—N-piperidine 73 4ad SPH-1099 TK 80-3 —CH₂—CN 73 8ac SPH-1312 DD24 —(CH2)3-(2-(4-F-phenyl)-2,5- diazabicyclo[2.2.1]heptane)-5-yl) 74 4agSPH-1098 Ro 11 —(CH2)2—N-morpholine 75 9a SPH-1284 DD 10 —CO—NHCH(Me)276 9b SPH-1283 DD 9 —CO—NHC(Me)3 77 9c SPH-1118 Ro 22—(CH2)2—N-morpholine 78 9d SPH-1330 RMA-15 —(CH2)3—NMe2 79 9e SPH-1333RMA 14 —(CH2)3—N-piperidine[Key:]Galanthamin Derivate = galanthamine derivatives[Key:]Beispiel = Example—CONH-2-naphthaline = —CONH-2-naphthalene

EXAMPLE 8 Step 1(6R)-1-Bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef[2]benzazepin-6-one(2a)

Water (660 ml) and concentrated hydrochloric acid (400 ml) were added toa stirred solution of(6R)-5,6,9,10,11,12,1-bromo-3-methoxy-6-oxo-4aH-hexahydro-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxaldehyde(2) (100.0 g, 0.26 mol) in toluene (2.6 l). The reaction mixture wasrefluxed for 48 hours while being stirred. The precipitate was filteredoff and washed with water (3×500 ml). The phases of the hydrate wereseparated, and the organic phase was extracted with water (3×500 ml).The precipitate was heated with the combined, aqueous solutions of thehydrate and hot-filtered. The solution was set at pH=12 with 30% sodiumhydroxide. The precipitate was filtered and dried (50° C./50 mbar) toobtain 64.5 g (70%) of title compound (2a) at about a melting point of228-231° C. ¹H-NMR (CDCl₆ δ 6.94 (dd, J₁=10.3, 1.9 Hz, 1H), 6.62 (s,1H), 6.00 (d, J=10.5 Hz, 1H), 4.69 (m, 1H), 4.04 (d, J=15.9 Hz, 1H),3.83 (d, J=15.9 Hz, 1H), 3.80 (s, 3H), 3.29 (m, 2H), 3.07 (d, J=1.9 Hz,1H), 2.70 (dd, J₁=17.8 Hz, J₂=3.7 Hz, 1H), 2.16 (m, 1H), 1.80 (dt,J₁=14.0 Hz, J₂=2.9 Hz, 1H); ¹³C-NMR (CDCl₃) δ 194.3 (s), 146.9 (s),143.8 (s), 135.3 (d), 130.6 (s), 129.3 (s), 126.9 (d), 121.9 (d), 111.8(s), 87.9 (d), 56.3 (t), 55.9 (q), 51.8 (t), 49.0 (s), 37.2 (t), 33.0(t). Anal. (C₁₆H₁₆BrNO₃.O.4H₂O) C, H, N.

Step 2(6R)-1-Bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef[2]benzazepin-6-ol(3)

An L-selectride solution (1 M, 276 ml, 0.276 mol) was added at −10° C.to a solution of(6R)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef][2]benzazepin-6-one(2a) (64.5 g, 0.184 mol) in dry THF (1.3 l). After 30 minutes ofstirring at −10 to −5° C., the reaction mixture was hydrolyzed with MeOH(80 ml) and concentrated by evaporation. The residue that was obtainedwas dissolved in 2N hydrochloric acid and stirred for 18 hours at roomtemperature. The solution was set at pH=9 with concentrated ammonia andextracted with EtOAc (3×500 ml), the combined, organic layers werewashed with brine and dried (Na₂SO₄) to produce 55.9 g (90.6%) of theproduct. ¹H-NMR (CDCl₃) δ 6.85 (s, 1H), 6.05 (m, 2H), 4.56 (b, 1H), 4.48(d, J=14.7 Hz, 1H), 4.10 (m, 1H), 3.85 (d, J=14.7 Hz, 1H), 3.80 (s, 3H),3.35-3.05 (m, 2H), 2.62 (m, 1H), 2.25 (m, 1H), 1.98 (d, J=13.2 Hz, 1H),1.85-1.65 (m, 2H); ¹³C-NMR (CDCl₃) δ 145.8 (s), 144.0 (s), 134.1 (s),131.6 (s), 127.9 (d), 126.8 (d), 115.5 (d), 113.0 (s), 88.4 (d), 61.7(d), 56.0 (q), 52.7 (t), 49.3 (s), 46.6 (t), 29.7 (t).

Step 3(6R)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(=(+/−)norgalanthamine) (4)

Activated zinc (89.0 g, 1.36 mol) and calcium chloride (44.0 g, 0.40mol) were added to a solution of(6R)-1-bromo-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(3) (20.0 g, 56.8 mmol) in 50% EtOH (1000 ml). The reaction mixture wasrefluxed for 18 hours and filtered on Celite. The filtrate wasconcentrated by evaporation, the residue was diluted with 2Nhydrochloric acid (500 ml) and extracted with EtOAc (3×400 ml). The pHof the aqueous phase was set at above 8.5 with concentrated ammonia andextracted with CH₂Cl₂ (3×100 ml) and with CH₂Cl₂:MeOH=9:1 (3×100 ml).The combined organic extracts were washed with brine (200 ml), dried(Na₂SO₄) and concentrated by evaporation to produce 12.3 g (79.0% ofcompound 4: ¹H-NMR (CDCl₃) δ 6.62 (b, 2H), 6.02 (m, 2H), 4.61 (b, 1H),4.14 (t, J=4.3 Hz, 1H), 3.98 (d, J=5.0 Hz, 2H), 3.83 (s, 3H), 3.30 (m,1H), 2.69 (t, J=15.7, 1H), 2.10-1.63 (m, 4H); ¹³C-NMR (CDCl₃) δ 146.2(s), 144.1 (s), 133.1 (s), 131.7 (s), 127.8 (d), 126.8 (d), 120.8 (d),111.1 (d), 88.4 (d), 61.9 (d), 55.9 (q), 53.3 (t), 48.5 (s), 46.7 (t),39.4 (t), 29.9 (t).

Anal. (C₂₀H₂₆N₂O₄) C, H, N.

Step 4Methyl(6R)-1-bromo-N¹¹-cyano-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)carboximidothioate(3bi)

0.21 g, 1.4 mmol) of N-cyanodithiocarbonimidic acid dimethyl ester (0.21g, 1.4 mmol) was added to a solution of (+/−)-norgalanthamine (0.5 g,1.4 mmol) in EtOH:DMF=4:1 (20 ml). The reaction mixture was refluxed for4 days and concentrated by evaporation. The residue was crystallized inEtOH to produce 0.25 g (41.7%) of compound 3bi: ¹H-NMR (CDCl₃): δ 6.90(s, 1H) 6.05 (dd, J₁=10.3 Hz, J₂=5.0 Hz, 1H), 5.86 (d, J=10.3 Hz, 1H),5.62 (d, J=16.5 Hz, 1H), 4.62 (b, 1H), 4.36 (d, J=16.5, 1H), 4.14 (m,1H), 3.83 (s, 3H), 3.79 (m, 1H), 2.96 (d, J=15.3 Hz, 1H), 2.77 (s, 3H),2.68 (m, 1H), 1.92 (m, 3H); ¹³C-NMR (CDCl₃): δ 146.3 (s), 145.0 (s),132.7 (s), 129.0 (s), 125.4 (d) 125.2 (d), 125.2 (s), 116.0 (d), 114.3(d), 88.0 (d), 61.3 (d), 56.1 (q), 55.0 (t), 49.6 (t), 48.6 (s), 29.4(t), 16.1 (q).

Anal. (C₁₉H₂₀BrN₃O₃S.0.85 EtOH) C, H, N.

EXAMPLE 9(6R)-3-Methoxy-11-(2-pyrimidinyl)-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef[2]benzazepin-6-ol(4a)

0.21 g, 1.8 mmol) of 2-chloropyrimidine and sodium bicarbonate (0.61 g,7.2 mmol) were added to a solution of (+/−)-norgalanthamine (0.5 g 1.8mmol) in EtOH (30 ml). The reaction mixture was refluxed for 2 days andconcentrated. The residue was diluted with water (30 ml), and EtOAc(3×20 ml) was extracted. The combined, organic extracts were washed withcommon salt solution (20 ml), dried (Na₂SO₄) and concentrated byevaporation to produce 0.51 g (80.8%) of 4a: ¹H-NMR (DMSO-d) δ 7.82 (d,J=4.0 Hz, 2H), 6.42 (d, J=12.0 Hz 1H), 6.23 (d, J=12.0 Hz, 1H), 6.03 (t,J=4.0 Hz, 1H), 5.83 (d, J=8.0 Hz, 1H), 5.54 (dd, J₁=8.0 Hz, J₂=3.0 Hz,1H), 4.98 (d, J=14.0 Hz, 1H), 428 (d, J=16.0, 1H), 4.09 (b, 1H), 3.94(d, J=14.0 Hz, 1H), 3.72 (m, 1H), 3.38 (s, 3H), 3.21 (t, J=14.0 Hz, 1H),2.54 (d, J=12.0 Hz, 1H), 2.15 (m, 1H), 1.55 (m, 3H), ¹³C-NMR (DMSO-d) δ159.5 (s), 156.7 (2), 145.5 (s), 142.8 (s), 131.6 (s), 128.9 (s), 126.8(d), 126.1 (d), 120.8 (d), 109.9 (d), 108.8 (d), 86.8 (d), 61.3 (d),54.8 (q), 50.2 (t), 47.3 (s), 47.4 (t), 34.6 (t) 29.2 (t). Anal.(C₂₀H₂₁N₃O.15 EtOH) C, H, N.

EXAMPLE 10

(6R)-11-(2-Chloro-4-pyrimidinyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4b) was produced analogously to Example 9. Reaction time 40 hours,yield 0.62 g (88.6%). ¹H-NMR (CDCl₃) δ 7.84 (d, J=4.0 Hz, 1H), 6.88 (d,J=12.0 Hz, 1H), 6.69 (d, J=12.0 Hz, 1H), 6.05 (b, 2H), 5.90 (d, J=4.0Hz, 1H), 5.58 (b, 1H), 4.34 (m, 2H), 4.18 (b, 1H), 3.80 (s, 3H), 3.60(t, J=16.0 Hz, 1H), 2.73 (d, J=16.0 Hz, 1H), 2.39 (m, 1H), 2.04 (d, J=18Hz, 1H), 1.87 (m, 2H); ¹³C-NMR (CDCl₃) δ 160.5 (s), 158.4 (s), 157.0(s), 145.0 (s) 144.1 (s), 132.2 (s), 128.2 (d), 127.8 (s), 126.6 (d),126.1 (d), 111.0 (d), 107.1 (d), 88.1 (d), 61.6 (d), 55.8 (q), 53.8 (t)48.3 (s), 46.0 (t), 34.9 (t), 29.6 (t).

EXAMPLE 11(6R)-11-(2-Diethylamino)-4-pyrimidinyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro]3a,3,2-ef][2]benzazepin-6-ol(4c)

0.1 g (1.30 mmol) of potassium hydroxide was added to a solution ofcompound 4b (0.5 g, 1.30 mmol) in diethylamine (6 ml, 57.6 mmol). Thereaction mixture was refluxed for 22 hours and concentrated byevaporation. The residue was diluted with saturated solution ofpotassium carbonate (30 ml) and extracted with EtOAc (3×20 ml). Thecombined, organic phases were washed with common salt solution (20 ml),dried (Na₂SO₄) and concentrated by evaporation. Flash chromatographyyielded 0.21 g (38.5%) of 4c. Below, only the different NMR signals aredescribed: ¹H-NMR (CDCl₃) δ 2.97 (d, J=16.0 Hz, 4H), 1.34 (m, 6H);¹³C-NMR (CDCl₃) δ 36.3 (t), 14.0 (q)

EXAMPLE 12

(6R)-11-(2-(3-(Dimethylamino)propoxy)-4-pyrimidinyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4d): The production was carried out analogously to Example 11. Reactiontime 2 hours, yield 0.16 g (41.0%). Only the different NMR signals aredescribed: ¹H-NMR (CDCl₃) δ 4.34 (m, 2H), 2.28 (s, 6H), 2.00 (m, 4H);¹³C-NMR (CDCl₃) δ5.0 (t), 56.3 (t), 45.2 (q), 27.0 (t).

EXAMPLE 13

(6R)-11-(4,6-Dichloro-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4e): A solution of 2,4,6-trichloro-1,3,5-triazine (0.66 g, 3.7 mmol) inacetone (16 ml) was poured onto ice water (35 ml) and added in smallportions at 0° C. to (+/−)-norgalanthamine (1.0 g, 3.7 mmol). After theaddition of 2N-sodium hydroxide (2 ml), the reaction mixture wasrefluxed for 40 hours. The aqueous phase was extracted with EtOAc (3×30ml). The combined, organic phases were washed with common salt solution(30 ml), dried (Na₂SO₄) and concentrated by evaporation, to produce 0.90g (59.5%) of compound 4e: ¹H-NMR (CDCl₃) δ 6.82 (d, J=10.0 Hz, 1H), 6.63(d, J=10.0 Hz, 1H), 6.02 (b, 2H), 5.30 (d, J=11.0 Hz, 1H), 4.75 (d,J=16.0, 1H), 4.50 (b, 1H) 4.22 (d, J=11.0 Hz, 1H), 4.11 (b, 1H), 3.78(s, 3H), 3.59 (m, 1H), 3.06 (m, 1H), 2.61 (d, J=16.0 Hz, 1H), 1.90 (m,3H); ¹³C-NMR (CDCl₃) δ 207.0 (s) 171.2 (s), 163.7 (s), 146.2 (s), 143.9(s), 132.2 (d), 129.5 (s), 127.6 (s), 126.7 (d), 121.5 (d), 110.8 (d),88.0 (d), 61.7 (d), 55.7 (q), 51.8 (t), 48.2 (s), 43.4 (t), 35.9 (t),29.7 (t).

Compounds 4f-4i contain the basic galanthamine skeleton, such as 4e, butare different in the nitrogen substituent. Since the proton and carbonsignal of the galanthamine core are not significantly different, the NMRsignals of the nitrogen substituent are relayed below.

EXAMPLE 14

(6R)-11-(4,6-Bis-(diethylamino-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4f): A solution of compound 4e (0.30 g, 0.71 mmol) in 40 ml of acetonewas poured onto 100 ml of ice water, and at 0° C., a solution ofdiethylamine (5.7 ml, 54.7 mmol) in acetone (10 ml) was added. Thereaction mixture was refluxed for 2 hours and then poured onto 200 ml ofice water. The aqueous phase was extracted with 3×100 ml of EtOAc. Thecombined organic phases were washed with common salt solution (100 ml),dried on sodium sulfate and concentrated by evaporation. Flashchromatography yielded 0.17 g (47.8%) of compound 4f: ¹H-NMR (CDCl₃) δ3.54 (m, 8H), 1.18 (m, 12H); ¹³C-NMR (CDCl₃) δ 41.7 (t), 13.4 (q)

EXAMPLE 15

(6R)-11-(4,6-Diphenoxy-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4 g): 6.5 g (18.3 mmol) of 2,4,6-triphenoxy-1,3,5-triazine was added toa solution of (+/−)-norgalanthamine (1.0 g, 3.74 mmol) in dioxane (60ml). The reaction mixture was refluxed for 20 hours. The precipitate wasfiltered off and washed with dioxane. The filtrate was concentrated byevaporation, and flash chromatography yielded 0.91 g (45.9%) of compound4 g: ¹H-NMR (CDCl₃) δ 7.42-7.03 (m, 10H); ¹³C-NMR (CDCl₃) δ 172.1 and162.3 (s), 138.3 and 138.1 (d), 134.6 (d), 131.3 and 130.8 (d).

EXAMPLE 16

(6R)-11-(4,6-Bis-(2aminoethoxy)-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4H): The compound was produced according to the procedure indicated inExample 11, whereby the reaction time was 3 hours. 0.15 g (67.9%) ofcompound 4H was obtained. ¹H-NMR (CDCl₃) δ 3.64 (m, 4H), 3.42 (m, 4H);¹³C-NMR (CDCl₃) δ 61.3 (t), 42.1 (t).

EXAMPLE 17

(6R)-11-(4,6-Bis-(2-(dimethylamino)ethoxy)-1,3,5-triazine-2-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4i). According to the procedure indicated in Example 11, compound 4iwas obtained at a reaction time of 3 hours in a yield of 0.16 g (59.5%):¹H-NMR (CDCl₃) δ 4.12 (q, J=6.0 Hz, 4H), 2.29 (d, J=4.0 Hz, 12H), 1.29(m, 8H); ¹³C-NMR (CDCl₃) δ 65.6 (t), 56.0 (t), 45.2 (q), 29.2 (t).

EXAMPLE 18

2-Chloro-1-((6R)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-1-ethanone(4j): 0.82 g of chloroacetyl chloride (7.3 mmol) and 0.81 g (8.0 mmol)of triethylamine were added to a solution of (+/−)-norgalanthamine (2.0g, 7.3 mmol) in dry TRF (100 ml). The reaction mixture was refluxed for3 hours and concentrated by evaporation. The residue was diluted with 2Nhydrochloric acid (100 ml) and extracted with EtOAc (3×75 ml). Theaqueous phase was set at pH>8.5 with concentrated ammonia and extractedwith 3×75 ml of CH₂Cl₂. The combined, organic phases were washed withcommon salt solution, dried on sodium sulfate and concentrated byevaporation. Flash chromatography yielded 0.20 g (7.7% of compound 4j):¹H-NMR (CDCl₃) δ 6.78 (b, 1H), 6.12 (m, 2H), 5.30 (d, J=11.0 Hz, 1H),4.65 (m, 2H), 4.32-4.01 (m, 3H), 3.78 (s, 3H), 3.59 (m, 1H), 3.06 (m,1H), 2.61 (d, J=16.0 Hz, 1H), 1.90 (m, 3H), ¹³C-NMR (CDCl₃) δ 166.0 (s)146.2 (s), 144.9 (s), 132.3 (d), 128.3 (s), 127.3 (s), 126.0 (d), 120.2(d), 111.2 (d), 88.2 (d), 61.7 (d), 55.8 (q), 52.8 (t), 48.1 (S), 45.5(t) 41.4 (t), 35.4 (t), 29.6 (t).

EXAMPLE 19(6R)-6-Hydroxy-N¹¹-isopropyl-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef[2]benzazepine-11(12H)carboxamide(4l)

According to the procedure that is indicated in Example 11, 0.50 g ofcompound 4H was obtained at a reaction time of 4 hours with a meltingpoint of 106-108° C.: ¹H-NMR (CDCl₃) δ 6.68 (dd, J=10.3; 8.3 Hz, 2H),6.00 (m, 2H), 4.59 (b, 1H), 4.47 (d, J=16.4 Hz, 1H), 4.31 (d, J=16.4,1H), 4.16 (m, 1H), 3.86 (m, 1H), 3.83 (s, 3H), 3.36 (dt, J=12.6; 2.0 Hz,1H), 2.69 (dd, J 15.7; 3.4 Hz, 1H), 2.28 (d, J=11.3 Hz, 1H), 2.02 (m,1H), 1.88 (dd, J=12.3; 3.4 Hz, 1H), 1.77 m, 1H), 1.07 (dd, J=21.8; 6.4Hz, 6H); ¹³C-NMR (CDCl₃) δ 156.4 (s), 146.8 (s), 144.5 (s), 132.4 (s),129.0 (s), 127.9 (d), 126.4 (d), 120.1 (d), 111.0 (d), 88.3 (d), 61.7(d), 55.8 (q), 51.5 (t), 48.3 (s), 45.4 (t), 42.4 (d), 36.4 (t), 29.7(t), 23.3 (q), 23.1 (q). Anal. (C₂₀H₂₆N₂O₄), C, H, N.

Compounds 4m-4s contain the galanthamine skeleton such as 41, but aredifferent with respect to the nitrogen substituent. Since the proton andcarbon signals of the galanthamine core do not differ from one anothersignificantly, only the signals of the nitrogen substituent are relayedbelow.

EXAMPLE 20(6R)—N¹¹-t-Butyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef[2]benzazepine-11(12H)-carboxamide(4m)

Process according to Example 11, reaction time 3 hours, yield 0.57 g(85%); melting point 204-205° C.; ¹H-NMR (CDCl₃) δ 1.24 (s, 9H); ¹³C-NMR(CDCl₃) 156.4 (s), 50.7 (s), 29.3 (q) Anal. (C₂₁H₂₈N₂O₄) C, H, N.

EXAMPLE 21(6R)—N¹¹-Ethyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef[2]benzazepine-11(12H)-carboxamide(4n)

Process according to Example 11, reaction time 3 hours, yield 0.61 g(98%); melting point 137-139° C.; ¹H-NMR (CDCl₃) δ 3.14 (q, J=4.0 Hz,2H), 1.04 (t, J=10 Hz, 3H); ¹³C-NMR (CDCl₃) δ 157.0 (s), 35.6 (t), 15.3(q).

EXAMPLE 22(6R)—N¹¹-Cyclohexyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide(4o)

Process according to Example 11, reaction time 5 hours, yield 0.56 g(79%); melting point 225-228° C.; ¹H-NMR (CDCl₃) δ 1.24 (s, 9H); ¹³C-NMR(CDCl₃) δ 48.8 (d), 33.4 (t), 33.2 (t), 25.5 (t), 24.8 (t), 24.6 (t).

EXAMPLE 23(6R)-6-Hydroxy-3-methoxy-N¹¹-phenyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide(4p)

Process according to Example 11, reaction time 4 hours, yield 0.34 g(47%); melting point 198-199° C.; ¹H-NMR (CDCl₃) δ 7.24 (m, 4H), 6.99(q, J=4.2 Hz, 1H); ¹³C-NMR (CDCl₃) δ 154.5 (s), 138.7 (s), 128.7 (d),122.9 (d), 119.7 (d), Anal. (C₂₃H₂₄N₂O₄, H₂O) C, H, N.

EXAMPLE 24

(6R)—N¹¹-4-Chlorophenyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide(4q): Process according to Example 11, reaction time 5 hours, yield 0.16g (21%); ¹H-NMR (CDCl₃) δ 17.49-6.94 (m, 4H); ¹³C-NMR δ (CDCl₃) 154.1(s), 139.1 (s), 123.4 (s), 122.9 (d), 119.7 (d).

EXAMPLE 25

(6R)-6-Hydroxy-3-methoxy-N¹¹-(S)-(−)α-methylbenzyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide(4r): Process according to Example 11, reaction time 6 hours, yield 0.66g (58%); ¹H-NMR (CDCl₃) δ 7.21 (d, J=6.0 Hz, 4H), 7.17 (m, 1H), 4.91 (m,1H), 1.41 (dd, J=20.0; 12 Hz, 3H); ¹³C-NMR (CDCl₃) δ 156.6 and 165.4(s), 144.5 (s), 128.3 and 128.1 (d), 126.5 and 126.4 (d), 125.9 and125.5 (d), 46.1 (d), 22.9 and 22.6 (q).

EXAMPLE 26

(6R)-6-Hydroxy-3-methoxy-N¹″-(s)-(−)α-methylbenzyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide(4s): Process according to Example 11, reaction time 6 hours, yield 0.66g (58%); ¹H-NMR (CDCl₃) δ 7.82 (d, J=8.0 Hz, 1H), 7.61 (d, J=6.0 Hz,2H), 7.43 (m, 4H); ¹³C-NMR (CDCl₃) δ 155.4 (s), 134.0 (s), 133.6 (s),132.5 (s), 128.6 (d), 127.9 (d), 125.9 (d), 125.7 (d), 125.6 (d), 125.6(d), 121.1 (d).

EXAMPLE 27(6R)-6-Hydroxy-3-methoxy-N¹¹-methyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carboxamide(4t)

Process according to Example 11, reaction time 3 hours, yield 0.57 g(99%); melting point 219-221° C.; ¹H-NMR (CDCl₃) δ 6.81 (d, J=8.3 Hz,1H), 6.71 (d, J=8.1 Hz, 1H), 6.12 (d, J=10.3 Hz, 1H), 5.81 (dd, J=10.2;4.4 Hz), 1H), 5.21 (d, J=15.8 Hz, 1H), 4.44 (s, 1H), 4.25 (d, J=5.5,1H), 4.07 (b, 1H), 3.72 (s, 3H), 3.66 (m, 1H), 2.84 (d, J=3.4 Hz, 3H);2.28 (d, J=11.2 Hz, 1H), 2.04 (d, J=20.1 Hz, 1H), 1.88 (d, J=12.1 Hz,1H), 1.65 (d, J=13.9 Hz, 1H); ¹³C-NMR (CDCl₃) δ 182.2 (s), 147.2 (b),144.9 (s), 132.4 (s), 128.2 (d), 126.6 (s), 126.2 (d), 120.5 (d), 111.3(d), 88.3 (d), 61.7 (d), 55.9 (q), 53.7 (t), 50.5 (t), 48.2 (s), 35.6(t), 32.9 (q) 29.7 (t). Anal. (C₁₈H₂₂N₂O₃S.O.05 CH₃C₆H₅) C, H, N.

EXAMPLE 28

(6R)-6-Hydroxy-3-methoxy-N¹¹-allyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11-(12H)-carbothioamide(4u): Process according to Example 11, reaction time 5 hours, yield 0.47g (70%); melting point 192-194° C.; same skeleton as 47, only thedifferent NMR signals are relayed: ¹H-NMR (CDCl₃) δ 6.85 (m, 1H), 5.13(m, 2H), 4.14 (m, 2H); ¹³C-NMR (CDCl₃) δ 181.2 (s), 133.7 (d), 116.6(t), 48.3 (t). Anal. (C₂₀H₂₄N₂O₃S) C, H, N.

EXAMPLE 29

((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef](2]benzazepine-11-(12H)-yl-fumaricacid dimethyl ester (4v): Process according to Example 11. 0.37 g (2.61mmol) of but-2-enedionic acid dimethyl ester was added to a solution of(+/−)-norgalanthamine (0.5 g, 1.74 mmol) in 40 ml of CH₂Cl₂, and it wasstirred for 20 hours. The solvent was removed to obtain an oily product,whose flash chromatography yielded 0.28 g (39.1%) of 4v.

Melting point 112-115° C., ¹H-NMR (CDCl₃) δ 6.63 (dd, J₁=12.6 Hz, J₂=8.1Hz, 2H), 6.02 (dd, J₁=15.9 Hz, J₂=11.5 Hz, 2H), 4.77 (b, 1H), 4.59 (b,1H), 4.22 (d, J=15.9, 1H), 4.13 (b, 1H), 3.92 (s, 3H), 3.83 (s, 3H),3.72 (d, J=15.9 Hz, 1H), 3.59 (s, 3H); 3.46 (m, 1H), 3.19 (dt, J₁=15.1Hz, J₂=3.1 Hz, 3H), 2.68 (dd, J₁=15.8 Hz, J₂=2.2 Hz, 1H), 2.00 (m, 1H),1.54 (m, 1H); ¹³C-NMR (CDCl₃) δ 167.6 and 165.7 (s), 153.0 (s), 146.0(s), 144.3 (s), 132.9 (s), 128.5 (s), 127.8 (d), 126.4 (d), 121.8 (d),111.2 (d), 88.6 (d), 86.6 (d), 61.9 (d), 56.9 (t), 55.8 (q), 55.0 (q)50.2 (q), 48.3 (s), 33.0 (t), 29.3 (t). Anal. (C₂₂H₂₅NO₇) C, H, N.

EXAMPLE 30

(6R)-11-(3-2-(4-Fluoro)phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl-propyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4w): Process according to Example 11, reaction time 4 days, yield 0.14g (63.0%); ¹H-NMR (CDCl₃) δ 7.21 (m, 2H); 6.68 (m, 3H), 5.0 (s, 1H),4.47 (d, J=14.0 Hz, 1H), 3.90 (m, 1H), 3.63 (m, 3H), 3.24 (m, 1H), 2.04(m, 3H); ¹³C-NMR (CDCl₃) 168.0 and 167.6 (s), 146.4 (d), 144.1 (s),127.7 and 127.5 (d), 112.5 and 112.4 (d), 67.0 (t), 57.0 and 56.8 (d),56.8 and 56.6 (t), 51.8 and 51.6 (t), 36.6 (t); 33.7 and 33.6 (t).

EXAMPLE 31

2-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-ylmethylene)-malononitrile(4×): Process according to Example 11, reaction time 6 hours, yield 0.41g (64.8%); ¹H-NMR (CDCl₃) δ 7.12 (m, 1H), 6.63 (dd, J₁=12.6 Hz, J₂=8.1Hz, 2H), 6.02 (dd, J₁=15.9 Hz, J₂=11.5 Hz, 2H), 4.59 (b, 1H), 4.22 (d,J=15.9, 1H), 4.13 (b, 1H), 3.83 (s, 3H), 3.72 (d, J=15.9 Hz, 1H), 3.46(m, 1H), 3.19 (dt, J₁=15.1 Hz, J₂=3.1 Hz, 3H), 2.68 (dd, J₁=15.8 Hz,J₂=2.2 Hz, 1H), 2.00 (m, 1H), 1.54 (m, 1H); ¹³C-NMR (CDCl₃) δ 157.2 and156.8 (d), 146.0 (s), 144.3 (s), 132.9 (s), 128.5 (s), 127.8 (d), 126.4(d), 124.2 (s), 121.8 (d), 116.8 and 116.5 (s), 115.0 and 114.7 (s),111.2 (d), 88.6 (d), 61.9 (d), 56.9 (t) 55.8 (q), 48.3 (s), 33.0 (t),29.8 (t).

EXAMPLE 32

2-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-ylmethylene)-malonicacid diethyl ester (4y): Process according to Example 11, reaction time21 hours, yield 0.46 g (63.3%), melting point 145-146° C., same skeletonas compound 4v, only the different NMR signals are described: ¹H-NMR(CDCl₃) δ 6.83 (s, 1H), 3.43 (m, 6H); ¹³C-NMR (CDCl₃) δ 181.2 (s), 133.7(d), 116.6 (t), 48.3 (t). Anal. (C₂₂H₂₅NO₇0.25 C₆H₁₄O) C, H, N.

EXAMPLE 33

3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl-acrylicacid ethyl ester (4z): Process according to Example 11, reaction time 20hours, yield 0.30 g (46.2%), melting point 121-122° C., same skeleton ascompound 4v, only the different NMR signals are described: ¹H-NMR(CDCl₃) δ 7.40 (dd, J₁=16.0 Hz, J₂=2.0 Hz, 1H), 4.68 (d, J=16.0 Hz, 1H),4.10 (m, 2H), 1.28 8 m, 3H); ¹³C-NMR (CDCl₃) δ 169.3 and 167.8 (s),161.1 (d), 97.5 (d), 59.0 (t), 14.5 and 14.3 (q).

Process E: A solution (+/−)-norgalanthamine (0.5 g, 1.83 mmol), 0.51 g(3.66 mmol) of potassium carbonate, (2.20 mmol) of sodium iodide andalkyl halide (2.20 mmol) in acetone (20 ml) were refluxed for 12 hoursand concentrated by evaporation. The residue was dissolved in 30 ml of2N hydrochloric acid and extracted with 1×20 ml of AcOEt. The aqueoussolution was set at pH>8.5 with concentrated ammonia and extracted withAcOEt (3×20 ml). The combined, organic extracts were washed with commonsalt solution, dried (Na₂SO₄), concentrated by evaporation and purifiedby MPLC.

Compounds 4ab-4ah and 4an-4aq contain the basic galanthamine skeletonsuch as 4aa, but are different with respect to the nitrogen substituent.Since the proton and carbon signals of the galanthamine core are notessentially different from one another, only the NMR signals of thenitrogen substituent are relayed below.

EXAMPLE 34Ethyl-2-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)acetate(4ac)

According to process e with use of ethyl chloroacetate and a reactiontime of 1 hour, 0.48 g of the compound (73%) was obtained; ¹H-NMR(CDCl₃) δ 4.10 (m, 2H), 3.32 (s, 2H), 1.21 (t, J=7.3 Hz, 3H); ¹³C-NMR(CDCl₃) δ 170.7 (s), 60.4 (t), 58.0 (t), 14.1 (q).

EXAMPLE 35

Instructions:

Substitution in Position 1

Direct Introduction of New Substituents

3.2.1.1 [4aS-(4αa,6β,8aR*)]-4a,5,9,10,11,12-Hexahydro-1-(N,N-dimethylamino)-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-(N,N-dimethylamino)-galanthamine (MH-7)

 320 mg (1.06 mmol) 1-aminogalanthamine (4) 0.50 ml formic acid in 2 mlof water 0.25 ml formaldehyde (37%)

While being stirred with a magnet, all reactants, dissolved in 10 ml ofwater, were heated together to 70° C. After 4.5 hours, it was made basicwith concentrated aqueous ammonia, whereby a white precipitate in yellowsolution precipitated. The reaction mixture was exhaustively extractedwith ethyl acetate, the combined organic phases were dried on sodiumsulfate, filtered, and the solvent was drawn off.

The resulting substance mixture was separated on a silica gel column(CHCL₃:MeOH=1:1) and then distilled under high vacuum by means of a bulbtube.

Yield: 0.17 g (0.52 mmol=49% of theory) of a light yellow oil

C₁₉H₂₆N₂O₃ [330.43]

TLC: R_(f)=0.49 (CHCl₃:MeOH=1:1)

Boiling point: 180° C./0.01 Torr

αD²⁰ [c=0.1, CHCl₃]=−156.36°

FID Numbers:

¹H: MHEMOF.016, ¹³C: MHEM1F.002, DEPT: MHEM2F.002

¹H-NMR (200 MHz, CDCl₃): δ 6.57 (s, 1H), 6.08 (dd, J=10.3, 1.0 Hz, 1H),5.97 (dd, J=10.3, 4.8 Hz, 1H), 4.56 (bs, 1H), 4.45 (d, J=15.1 Hz, 1H),4.12 (bs, 1H), 3.83 (s, 3H), 3.55 (d, J=15.1 Hz, 1H), 3.12 (td, J=13.1,1.7 Hz, 1H), 2.97 (dt, J=14.1, 3.5 Hz, 1H), 2.72-2.53 (m, 1H), 2.58 (s,6H), 2.44 (s, 3H), 2.12-1.98 (m, 2H), 1.62 (ddd, J=13.6, 3.8, 2.1 Hz,1H); ¹³C-NMR (50 MHz, CDCl₃): δ 147.1 (s), 143.2 (s), 142.0 (s), 133.7(s), 127.3 (d), 127.2 (d), 124.2 (s), 103.9 (d), 88.3 (d), 62.0 (d),55.9 (q), 54.4 (t), 54.1 (t), 48.4 (s), 45.7 (q), 44.2 (q), 34.8 (t),29.8 (t)

EXAMPLE 37

(4aS,6R,8aS)-11-(3-Aminoethyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4af), Process F, reactant compound 4ad, reaction time 1 hour; yield0.31 g (59.2%); melting point 47-51° C.; ¹H-NMR (CDCl₃) δ 2.69 (m, 2H),1.92 (b, 2H); ¹³C-NMR (CDCl₃) δ 51.9 (s), 38.0 (t).

EXAMPLE 40

Ethyl-3-((6R)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanoate(4ai): Process B, reaction time 4 hours; yield 0.64 g (47.5%); ¹H-NMR(CDCl₃) δ 4.15 (q, J=6.0 Hz, 2H), 2.81 (t, 7.0 Hz, 2H), 2.47 (t, J=7.0Hz, 2H), 1.23 (t, J=6 Hz, 3H); ¹³C-NMR (CDCl₃) δ 172.4 (s), 60.3 (t),57.3 (t), 32.9 (t), 14.1 (q).

EXAMPLE 41

t-Butyl-3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanoate(4aj): Process B, reaction time 5 hours; yield 0.83 g (60.0%); ¹H-NMR(CDCl₃) δ 2.82 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 1.43 (S, 9H);¹³C-NMR (CDCl₃) δ 172.0 (s), 80.5 (s), 57.7 (t), 34.2 (t), 28.0 (q).Anal. (C₂₄H₃₃NO₅) C, H, N.

EXAMPLE 42

3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,2,2-ef][2]benzazepine-11(12H)-yl)-N¹¹-isopropylpropanamide(4ak): Process B, reaction time 18 hours; yield 0.55 g (78.7%); ¹H-NMR(CDCl₃) δ 3.81 (m, 1H), 2.79 (t, J=6 Hz, 2H), 2.32 (t, J=6.0 Hz, 2H),1.10 (t, J=12.0 Hz, 6H); ¹³C-NMR (CDCl₃) δ 171.4 (s), 56.9 (t), 40.7(d), 33.2 (t), 22.7 (q).

EXAMPLE 43

3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-N1-t-butylpropanamide(4al): Process B, reaction time 24 hours; yield 0.37 g (51.2%); ¹H—NMR(CDCl₃) δ 2.76 (t, 6.0 Hz, 2H), 2.29 (m, 2H), 1.28 (s, 9H); ¹³C-NMR(CDCl₃) δ 171.4 (s), 51.4 (t), 50.3 (s), 33.5 (t) 28.7 (q).

EXAMPLE 44

3-((6R)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanitrile(4 am): Process B, reaction time 4 hours; yield 0.53 g (90.6%); ¹H-NMR(CDCl₃) δ 2.82 (t, J=7.1 Hz, 2H), 2.47 (t, J=6.8 Hz, 2H); ¹³C-NMR(CDCl₃) δ 118.7 (s), 51.6 (t), 46.6 (t), 16.7 (t).

EXAMPLE 45

(6R)-11-(3-Hydroxypropyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4an): Process F, reactant compound 4ai, reaction time 7 hours; yield0.21 g (47.7%); ¹H-NMR (CDCl₃) δ 3.77 (m, 2H), 2.72 (m, 2H), 2.02 (m,2H); ¹³C-NMR (CDCl₃) δ 63.9 (t), 57.3 (t), 29.8 (t).

EXAMPLE 46

(6R)-11-(3-Aminopropyl)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4ao): Process F, reactant compound 4 am, reaction time 1 hour; yield 78mg (52.8%); ¹H-NMR (CDCl₃) δ 3.22 (m, 2H), 2.68 (m, 2H), 1.72 (m, 2H);¹³C-NMR (CDCl₃) δ 51.3 (t), 37.8 (t), 29.3 (t).

EXAMPLE 47

(6R)-11-(3-Piperidine-1-yl-propyl)-3-methoxy-5,6,9,10-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(4ap): Process e, reaction time 3 days; yield 0.36 g (53.2%); ¹H-NMR(CDCl₃) δ 2.68 (m, 8H), 1.77 (m, 6H), 1.50 (m, 2H); ¹³C-NMR (CDCl₃) δ57.4 (t) 44.1 (t), 49.2 (t), 24.7 (t), 23.4 (t), 23.3 (t).

EXAMPLE 48 Step 1(4a,S,6R8aS)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef[2]benzazepin-6-ol,(−)-norgalanthamine (8)

Method 1:

A solution of 7.72 g (20.0 mmol) of (+)-O,O-di-p-toluoyl tartaric acidin 15 ml of methanol is added in drops to a solution of 10.92 g (40.0mmol) of rac.norgalanthamine (4) in 40 ml of methanol, and it is thenrewashed with 1 ml of methanol. The solution is mixed with a seedcrystal (without a seed crystal, crystal formation can take severalweeks), and it is allowed to stand for two days at 4° C. Then, it isthoroughly ground with a glass rod and allowed to stand for another twoto five days at 4° C., whereby it is always thoroughly ground again witha glass rod. Then, the precipitated salt is suctioned off, rewashedthree times with ice-cold methanol and taken up in 100 ml of water. Theaqueous phase is made basic with concentrated aqueous ammonia andextracted three times with 60 ml each of ethyl acetate. The combinedorganic phases are washed once with saturated aqueous sodium chloridesolution, dried (Na₂SO₄, activated carbon), filtered and concentrated byevaporation, by which 2.9 g (37.5% of theory) of colorless crystals isobtained on (−)-norgalanthamine (8).

Method 2:

m-CPBA (peroxide content 76%, 15.6 g 70 mmol) was added to a solution ofgalanthamine (1) (20.0 g, 70 mmol) in CH₂Cl₂ (350 ml), and the clearsolution was stirred for 40 minutes at room temperature. In this stage,the conversion into the N-oxide was quantitative, as was found by HPLC.Then, a solution of FeSO₄.7H₂O (9.7 g 35 mmol) in MeOH (100 ml) wasadded. The mixture was stirred for 20 minutes, mixed with 2Nhydrochloric acid (200 ml), the volatile portions (CH₂Cl₂ and MeOH) wereevaporated at reduced pressure and then washed with ether (3×100 ml).The aqueous solution was set at pH>8.5 with concentrated ammonia andextracted with CH₂Cl₂ (3×100 ml) and with CH₂Cl₂:MeOH=9:1 (3×100 ml).The combined, organic extracts were washed with common salt solution(200 ml), dried on Na₂SO₄ and concentrated by evaporation to produce acrystalline product (18.2 g, 96%), which consisted of a 92:8 mixture ofnorgalanthamine and galanthamine. MPLC (CHCl₃:MeOH:Et₃N=98:1.25:0.5),16.1 g (84.7%) of norgalanthamine (8): ¹H-NMR (CDCl₃) δ 6.62 (b, 2H),6.02 (m, 2H), 4.61 (b, 1H), 4.14 (t, J=4.3 Hz, 1H), 3.98 (d, J=5.0 Hz,2H), 3.83 (s, 3H), 3.30 (m, 1H), 2.69 (d, J=15.7, 1H), 2.10-1.63 (m,4H); ¹³C-NMR (CDCl₃ δ 146.2 (s), 144.1 (s), 133.1 (s), 131.7 (s), 127.8(d), 126.8 (d), 120.8 (d), 111.1 (d), 88.4 (d), 61.9 (d), 55.9 (q), 53.3(t), 48.5 (s), 46.7 (t), 39.4 (t), 29.9 (t).

Step 2

(4a,S,6R₈aS)-3-Methoxy-11-phenyl-5,6,9,10,11,12-hexahydro-4aH[1]benzofuro[3a,3,2-ef[2]benzazepin-6-ol(8a). 0.28 g of phenylboric acid (7.2 mmol), 0.6 ml of pyridine (7.2mmol), 0.67 g of copper acetate (3.6 mmol) and one molecular sieve (1.0g) were added to a solution of 1.0 g of compound 8 (−)-norgalanthaminein 50 ml of CH₂Cl₂. The reaction mixture was stirred at room temperaturefor 3 days. The precipitate was filtered off and washed with 3×10 ml ofCH₂Cl₂. The filtrate was extracted 3× with 50 ml of dilute ammoniasolution. The combined, aqueous phases were extracted with 3×50 ml ofCH₂Cl₂, the organic phases were washed with common salt solution, driedon sodium sulfate and concentrated by evaporation. MPLC yielded 0.33 g(26.4%) of compound 8a. Melting point 178-180° C.;

¹H-NMR (CDCl₃) δ 7.18 (m, 2H), 6.82 (m, 3H), 6.67 (dd, J₁=33.8 Hz,J₂=7.6 Hz, 2H), 6.05 (b, 2H), 4.66 (b, 1H), 4.53 (m, 1H), 4.19 (d,J=15.3 Hz, 1H), 3.85 (s, 3H), 3.81 (d, J=15.3 Hz, 1H), 3.33 (m, 1H),2.68 (m, 1H), 2.07 (m, 3H), 1.62 (m, 1H); ¹³C-NMR (CDCl₃ δ 158.2 (s),145.9 (s), 144.5 (s), 133.0 (s), 129.4 (s), 128.9 (d), 128.1 (d), 126.9(d), 126.1 (d), 121.1 (d), 116.0 (d), 111.4 (d), 88.6 (d), 61.9 (d),57.0 (t), 55.9 (q), 50.6 (t) 48.2 (s), 32.8 (t), 29.9 (t). Anal.(C₂₂H₂₃NO₃.0.75 H₂O) C, H, N.

EXAMPLE 49

(4a,S,6R,8aS)-3-Methoxy-11-thiophenyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8b). The compound was produced as in compound 8a, and the reaction timewas 3 days, yield 0.14 g (28.0%). Only the NMR signals that aredifferent from 8a are described: 1H-NMR (CDCl₃) 7.23 (m, 1H), 6.92 (t,J=3.0 Hz, 1H), 6.83 (d, J=2.7 Hz, 1H); ¹³C-NMR (CDCl₃ δ 145.7 (s), 127.6(d), 126.2 (d), 125.0 (d). Anal. (C₂₀H₂₁NO₃S) C, H, N.

EXAMPLE 50

(4a,S,6R,8aS)-11-Benzoyl-piperidine-4-yl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8c). 1-Benzoyl-piperidin-4-one (0.34 g, 1.7 mmol), 0.47 g of titaniumisopropylate (1.7 mmol) and 3.6 g (1.3 mmol) of compound 8 were meltedfor 30 minutes at 110° C. After cooling at room temperature, a solutionof sodium cyanoborohydride (65 mg, 0.9 mmol) in dry EtOH (10 ml) wasadded, and the reaction mixture was stirred at room temperature for 24hours. After 2 ml of water was added, the precipitate was filtered off,the filtrate was concentrated by evaporation, and the residue wasdiluted with 20 ml of EtOAc and filtered again. The clear solution wasconcentrated by evaporation. MPLC yielded 0.24 g (38.8%) of compound 8c.¹H-NMR (CDCl₃) δ 7.52-7.31 (m, 5H), 6.65 (b, 2H), 6.08 (m, 2H), 4.64 (b,1H), 4.22-3.90 (m, 4H), 3.82 (s, 3H), 3.37 (m, 2H), 3.01-2.62 (m, 5H),2.10-1.82 (m, 5H), 1.67-1.42 (m, 2H); ¹³C-NMR (CDCl₃) 170.1 (s), 145.8(s), 144.0 (s), 136.0 (s), 133.1 (s), 129.4 (d), 128.8 (d), 128.4 (d),128.3 (d), 127.6 (d), 126.7 (d), 121.6 (d), 111.2 (d), 88.6 (d), 61.9(d), 55.8 (q), 55.6 (t), 48.3 (t), 30.8 (t), 29.8 (t).

EXAMPLE 51

(4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxylicacid phenyl ester (8e): 2.5 g of sodium bicarbonate (29.8 mmol) and 1.84ml of phenyl chloroformate (14.6 mol) were added to a solution of 0.50 gof compound 8 (1.74 mmol) in 50 ml of CHCl₃. The mixture was vigorouslystirred and refluxed for two hours and then diluted with water (30 ml).The phases were separated. The aqueous phase was extracted with 2×30 mlof CH₂ Cl₂, and the combined organic phases were washed with 1Nhydrochloric acid (30 ml), dried on sodium sulfate and concentrated byevaporation under reduced pressure to produce the crude product. MPLC(CH₂Cl₂:MeOH=99:1) yielded 0.58 g (84.2%) of compound 8e: 1H-NMR (CDCl₃)δ 7.51-7.04 (m, 5H), 6.82 (dd, J₁=24.0 Hz, J₂=6.0 Hz, 2H), 6.04 (b, 2H),4.91 (b, 1H), 4.69 (d, J=6.0 Hz, 2H), 4.20 (b, 1H), 3.83 (s, 3H), 3.42(m, 1H), 3.19 (m, 1H), 2.43-1.90 (m, 4H); ¹³C-NMR (CDCl₃) δ 151.3 (s),146.6 (s), 145.7 (s), 130.5 (s), 130.1 (s), 129.4 (d), 129.3 (d), 125.9(d), 125.3 (d), 125.0 (d), 121.6 (d), 111.9 (d), 88.3 (d), 62.8 (d),57.7 (t), 55.9 (q), 53.4 (t), 49.3 (s), 43.3 (t), 32.7 (t).

EXAMPLE 52

(4a,S,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carbothionicacid-O-phenyl ester (8f): 0.24 ml of chlorothionoformate (1.74 mmol) wasadded to a solution of 0.50 g of compound 8 (1.74 mmol) in 25 ml ofCHCl₃, and the reaction mixture was stirred for 1 hour under nitrogen.The solvent was separated to produce a colorless oil that wasflash-chromatographed to produce 0.50 g (71.2%) of compound 8a: ¹H-NMR(CDCl₃) δ 7.48-7.12 (m, 3H), 7.02 (d, J=6.0 Hz, 2H), 6.83 (m, 2H), 6.04(b, 2H), 5.08 (m, 1H), 4.71 (d, J=26.0 Hz, 2H), 4.28 (m, 1H), 3.88 (s,3H), 3.41 (m, 2H), 2.51-2.09 (m, 4H); ¹³C-NMR (CDCl₃) δ 187.5 and 187.4(s), 153.8 and 153.7 (s), 146.7 and 146.6 (s), 145.8 and 145.7 (s),131.3 and 130.6 (s), 130.2 and 129.5 (s), 129.2 and 129.1 (d), 126.0 and125.9 (d), 125.0 and 124.9 (d), 122.7 and 122.6 (d), 121.6 and 120.4(d), 115.3 (d), 112.0 (d), 84.4 and 84.2 (d), 63.1 and 62.9 (d), 55.9(q), 51.5 (t), 49.5 and 49.3 (s), 47.8 (t), 36.9 (t), 33.1 (t).

EXAMPLE 53

(4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxylicacid-9-H-fluor-9-ylmethyl ester (8 g): 0.5 g of9-fluorenylmethyloxycarbonyl chloride (20 mmol) was added to a solutionof 0.5 g of compound 8 (1.8 mmol) and 2.5 ml of triethylamine (1.8 mmol)in 20 ml of CH₂Cl₂, and it was stirred for 30 minutes at roomtemperature. The reaction mixture was concentrated by evaporation, theresidue was diluted with 80 ml of 2N hydrochloric acid and extractedwith 5×50 ml of CH₂Cl₂. The organic phases were combined, washed withcommon salt solution, dried on sodium sulfate and concentrated byevaporation to produce 0.88 g (99.2%) of compound 8 g. Melting point76-79° C.; α_(D)=−33.0°; ¹H-NMR (CDCl₃) δ 1.72 (dd, J=13.5; 5.0 Hz, 1H),1.80-2.10 (m, 2H), 2.69 (dd, J=13.5; 5.0 Hz, 1H), 3.20-3.45 (m, 2H),3.85 (s, 3H), 3.95-4.35 (m, 3H), 4.40-4.52 (m, 2H), 5.78-6.05 (m, 2H),6.22-6.82 (m, 2H), 7.19-7.82 (m, 8H); ¹³C-NMR (CDCl₃) δ 155.1 (s), 144.4(s), 144.0 (S), 141.4 (s), 134.0 (s) 129.1 (s), 128.1 (s), 128.0 (d),127.6 (d), 126.4 (d), 124.9 (d), 124.7 (d), 121.0 (d), 119.9 (d), 111.1(d), 88.3 (d), 66.9 (t), 61.9 (d), 56.0 (q), 51.5 (t), 48.3 (S), 47.3(d), 45.9 (t), 36.4 (t), 29.7 (t).

EXAMPLE 54

1-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef](2]benzazepine-11(12H)-yl)pent-4-en-1-one(8 h): 0.97 ml (5.1 mmol) of pent-4-enoic anhydride was added at 0° C.to a solution of 1.0 g of compound 8 (3.7 mmol) and 0.51 ml (3.7 mmol)of triethylamine in 40 ml of CH₂Cl₂MeOH=5:2, and it was stirred for 20minutes. The reaction mixture was diluted with 20 ml of CH₂Cl₂,extracted with 2×20 ml of saturated sodium bicarbonate solution. Thecombined aqueous phases were extracted with 2×40 ml of CH₂Cl₂, thecombined organic phases were washed with common salt solution, dried onsodium sulfate and concentrated by evaporation to produce 1.24 g (95.3%)of compound 8 h: ¹H-NMR (CDCl₃) δ 6.66 (b, 2H), 5.98 (m, 2H), 5.78 (m,1H), 4.98 (m, 2H), 4.66 (d, J=12.8 Hz, 1H), 4.55 (s, 1H), 4.41 (d,J=16.5 Hz, 1H), 4.11 (b, 1H), 3.93 (m, 1H), 3.81 (s, 3H), 3.17 (t,J=17.7 Hz, 1H), 2.76-2.15 (m, 5H), 1.92 (m, 3H); ¹³C-NMR (CDCl₃) δ 171.7(s), 146.8 (s), 144.6 (s), 137.3 (d), 132.4 (s), 128.1 (s), 128.0 (d),126.3 (d), 120.3 (d), 114.9 (d), 111.0 (d), 88.2 (d), 61.7 (d), 55.8(q), 52.7 (t), 48.2 (s), 44.6 (t), 35.7 (t), 33.2 (t), 29.7 (t), 28.8(t)

EXAMPLE 55

1-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2)benzazepine-11(12H)-carboxamide(8i): the pH was set at 3 with 2N hydrochloric acid in a suspension of0.5 g of compound 8 (1.8 mmol) in 25 ml of water, and 0.23 g (3.6 mmol)of sodium cyanide was added. The reaction mixture was stirred for 25hours at room temperature, and then the pH was set at above 8.5 withconcentrated ammonia and finally extracted with 3×20 ml of CH₂Cl₂. Thecombined, aqueous phases were extracted with common salt solution, driedon sodium sulfate and concentrated by evaporation. MPLC(CHCl₃:MeOH(NH₃)=95:5) yielded 0.38 g (66%) of compound 8i: ¹H-NMR(CDCl₃) δ 6.67 (dd, J=12.8; 8.1 Hz, 2H), 6.00 (dd, J=15.1; 10.4 Hz, 2H),4.68 (b, 1H), 4.51 (d, J=16.8 Hz, 1H), 4.31 (d, J=1.6.8 Hz, 1H), 4.11(m, 1H), 3.81 (s, 3H), 3.35 (t, J=12.8 Hz, 1H), 2.67 (d, J=15.3 Hz, 1H),2.41 (b, 1H), 1.97 (m, 2H), 1.72 (d, J=13.8 Hz, 1H); ¹³C-NMR (CDCl₃) δ158.1 (s), 146.8 (s), 144.5 (s), 132.3 (s), 128.6 (s), 128.0 (d), 126.2(d), 120.3 (d), 111.1 (d), 88.1 (d), 61.6 (d), 55.8 (q), 51.9 (t), 48.3(s), 45.6 (t), 36.3 (t), 29.7 (t).

EXAMPLE 56

(4a,S,6R,8aS)-6-Hydroxy-3-methoxy-N¹¹-methyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carbothioamide(8j): Process according to Example . . . , reaction time 4 hours, yield1.02 g (88%); melting point 229-230° C., ¹H-NMR and ¹³C-NMR wereidentical to compound 4t. Anal. C₁₈H₂₂N₂O₃S.O.2 CH₃C₆H₅C, H, N.

EXAMPLE 57

(4a,S,6R,8aS)-6-Hydroxy-N¹¹-isopropyl-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide(8k): Process A, reaction time 3 hours, yield 1.86 g (71%); ¹H-NMR and¹³C-NMR were identical to compound 4i.

EXAMPLE 58

(4a,S,6R,8aS)—N¹¹-t-Butyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide(8l): Process A, reaction time 3 hours, yield 1.63 g (60%); meltingpoint 106-108° C.; ¹H-NMR and ¹³C-NMR were identical to compound 4 m.

EXAMPLE 59

(4a,S,6R,8aS)-6-Hydroxy-3-methyl-N¹¹-2-trifluoromethyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide(8m): Process A, reaction time 5 hours, yield 0.60 g (59%);

¹H-NMR (CDCl₃) δ 8.20 (t, J=8.0 Hz, 1H), 7.24 (m, 2H), 7.02 (m, 1H);¹³C-NMR (CDCl₃) δ 153.6 (s), 137.6 (s), 127.6 (d) 126.1 (d), 123.0 and117.8 (s), 122.3 (d), 119.8 (s), 111.3 (d)

EXAMPLE 60

Methyl-(4a,S,6R,8aS)—N¹¹-Cyano-6-hydroxy-=3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboximidothioate(8n). The compound was produced as described for compound 3bi. Reactiontime 3 days, yield 0.90 g (33.2%); ¹H-NMR (CDCl₃) δ 6.72 (m, 2H), 5.98(d, J=10.2 Hz, 2H), 4.62 (m, 2H), 4.14 (b, 1H), 3.92 (d, J=11.8 Hz, 1H),3.84 (s, 3H), 3.44 (m, 2H), 2.74 (s, 3H), 2.68 (m, 1H), 1.99 (m, 3H);¹³C-NMR (CDCl₃) δ 146.2 (s), 144.9 (s), 131.7 (s), 128.7 (d), 125.8 (s),125.5 (d), 121.8 (d), 111.2 (d), 88.1 (d), 61.6 (d), 55.8 (q), 51.2 (t),49.7 (t), 47.9 (s), 29.6 (t), 16.1 (q).

EXAMPLE 61(4a,S,6R,8aS)-11-(Cyclopropylmethyl)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8o)

Process according to Example E, reaction time 36 hours, yield 0.12 g(29.0%); same skeleton as 4aa, only the different NMR signals aredescribed.

¹H-NMR (CDCl₃) δ 3.48 (t, J=8.0 Hz, 2H), 0.91 (m, 1H) 0.53 (d, J=12 Hz,2H), 0.11 (d, J=6 Hz, 2H); ¹³C-NMR (CDCl₃) δ 57.2 (t), 9.8 (d), 4.7 (t),4.1 (t).

EXAMPLE 63

3-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)ethanonitrile(8r): Process as in Example E, reaction time 2 hours, yield 1.67 g(61.1%); melting point 169-171° C.; ¹H-NMR and ¹³C-NMR were identical tocompound 4ad. Anal. (C₁₈H₂₀N₂O₃.O.67H₂O) C, H, N.

EXAMPLE 64

1-(2-Phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl)-2-((4a,S,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-1-ethanone(8s): Process as in Example E, reaction time 3 days, yield 0.68 g(37.8%); melting point 85-89° C.; α_(D)=−169.3°, same skeleton as 4aa,only different NMR signals are described: ¹H-NMR (CDCl₃) δ 7.21 (m, 2H);6.68 (m, 3H), 5.0 (s, 1H), 4.47 (d, J=14.0 Hz, 1H), 3.90 (m, 1H), 3.63(m, 3H), 3.24 (m, 1H), 2.04 (m, 3H); ¹³C-NMR (CDCl₃) δ 168.0 and 167.6(s), 146.4 (d), 144.1 (s), 127.7 (d), 127.5 (d), 112.5 (d), 112.4 (d),67.0 (t), 57.0 and 56.8 (d), 56.8 and 56.6 (t), 51.8 and 51.6 (t), 36.6(t); 33.7 and 33.6 (t). Anal. (C₂₉H₃₃N₃O₄.O.33H₂O) C, H, N.

EXAMPLE 65(4a,S,6R,8aS)-11-(3-Aminoethyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8t)

Process according to Example F, reactant compound 8r; reaction time 18hours, yield 1.01 g (66.1%); melting point 72-75° C.; α_(D)=−71.58°,¹H-NMR and ¹³C-NMR were identical to compound 4af. Anal.(C₁₈H₂₄N₂O₃.0.65 EtOH.0.05 CH₂Cl₂)) C, H, N.

EXAMPLE 66

(4a,S,6R,8aS)-11-(2-Morpholine-4-yl-ethyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8u): Process according to Example E, reaction time 2 days, yield 1.77 g(63.6%); melting point 101-104° C.; α^(D) ₂₀=−110.9°, ¹H-NMR and ¹³C-NMRwere identical to compound 4ag. Anal. (C₂₂H₃₀N₂O₄O.15 CH₂Cl₂) C, H, N.

EXAMPLE 67

(4a,S,6R,8aS)-11-(2-Phenyl-2,5-diazabicylo[2.2.1]heptane-5-yl-ethyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8v): Process according to Example F, reactant compound 8s, reactiontime 30 minutes, yield 0.26 g (50.8%); melting point 72-75° C.; α^(D)₂₀−131.6°, ¹H-NMR and ¹³C-NMR were identical to compound 4ah. Anal.(C₂₉H₃₅N₃O₃.0.35 CH₂Cl₂.0.5 Et₃N) C, H, N.

EXAMPLE 68

3-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanoicacid (8w): A solution of 8w (0.5 g, 1.25 mmol) was added to CH₂Cl₂ (20ml) in trifluoroacetic acid (5 ml). The reaction mixture was stirred atroom temperature for 2 hours and yielded a concentrate of 0.37 g (64.5%)of 8w: same skeleton as 4aa, only different NMR signals are described:¹H-NMR (CDCl₃) 8.95 (b, 1H), 2.82 (m, 2H), 2.25 (m, 2H).

EXAMPLE 69

t-Butyl-3-((4a,S,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef](2]benzazepine-11(12H)-propanoate(8×): Process B, reaction time 6 hours, yield 0.74 g (53.2%); ¹H-NMR and¹³C-NMR were identical to compound 4aj.

EXAMPLE 70

(4a,S,6R,8aS)-11-(3-Hydroxypropyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef](2]benzazepin-6-ol(8z); Process E, reaction time 4 days, yield 0.32 g (56.7%);α_(D)=90.0°; ¹H-NMR and ¹³C-NMR were identical to compound 4an.

EXAMPLE 71

(4a,S,6R,8aS)-11-((3-Dimethylamino)propyl-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8aα): Process E, reaction time 24 hours, yield 0.45 g (51.6%); sameskeleton as 4aa, only the different NMR signals are described.

¹H-NMR (CDCl₃) δ 2.50 (m, 2H), 2.30 (m, 2H), 2.22 (s, 3H), 2.18 (s, 3H),1.82 (m, 2H); ¹³C-NMR (CDCl₃) δ 55.6 (t), 53.4 (t), 45.0 (q); 25.3 (t).

EXAMPLE 72

(4a,S,6R,8aS)-3-Methoxy-11-(3-piperidine-1-yl-propyl)-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8ab): Process E, reaction time 3 days, yield 1.77 g (54.7%); meltingpoint 84-92° C.; α^(D) ₂₀=−50.64; ¹H-NMR and ¹³C-NMR were identical tocompound 4an. Anal. (C₂₄H₃₄N₂O₃.3C₄H₆O₆) C, H, N.

EXAMPLE 73(4a,S,6R,8aS)-11-(3-2-(4-Fluoro)phenyl-2,5-diazabicyclo[2.2.1]heptane-5-yl-propyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(8ac)

Process E, reaction time 4 days, yield 1.77 g (59.3%); melting point84-92° C.; α^(D) ₂₀=−50.64; ¹H-NMR and ¹³C-NMR were identical tocompound 4aq. Anal. (C₃₀H₃₆FN₃O₃.2CH₂Cl₂.2 Et₃N) C, H, N.

EXAMPLE 74

(4a,R,6S,8aR)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol,(+) norgalanthamine (9) was prepared and described for 8: yield 5.35 g(74.2%); ¹H-NMR and ¹³C-NMR were identical to compound 8.

EXAMPLE 75

(4a,R,6S,8aR)-6-Hydroxy-N¹¹-isopropyl-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide(9a): Process A, reaction time 3 hours; yield 1.03 g (79%); ¹H-NMR and¹³C-NMR were identical to compound 41.

EXAMPLE 76

(4a,R,6S,8aR)—N¹¹-t-Butyl-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxamide(9b): Process A, reaction time 3 hours; yield 0.85 g (63%); ¹H-NMR and¹³C-NMR were identical to compound 4m.

EXAMPLE 77

(4a,R,6S,8aR)-3-Methoxy-11-(2-morpholine-4-yl-ethyl)-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(9c): Process E, reaction time 2 days; yield 0.12 g (53.2%); ¹H-NMR and¹³C-NMR were identical to compound 4ag.

EXAMPLE 78

(4a,R,6S,8aR)-1-((3-Dimethylamino)propyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(9d): Process E, reaction time 22 hours; yield 0.19 g (44.6%); ¹H-NMRand ¹³C-NMR were identical to compound 8aa.

EXAMPLE 79

(4a,R,6S,8aR)-11-(3-Piperidine-1-yl-propyl)-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol(9e): Process E, reaction time 20 hours; yield 0.33 g (75.0%); ¹H-NMRand ¹³C-NMR were identical to compound 4ap.

EXAMPLE 80 Step 1 2-Bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde

2-Bromo-5-hydroxy-4-methoxybenzaldehyde (100.0 g, 433 mmol),2-bromopropane (160.0 g, 1.30 mol) and potassium carbonate (300 g, 2.16mol, anhydrous, freshly ground) are stirred in acetonitrile (1200 ml)for 48 hours at 60° C.

The reaction mixture is filtered, the solvent is distilled off in arotary evaporator, and the residue is dispersed between water (800 ml)and ether (800 ml). The aqueous phase is extracted with ether (2×300ml), the combined organic phases are washed with water (2×500 ml) andsaturated common salt solution (1×500 ml), dried (sodiumsulfate/activated carbon), filtered, and the residue that is obtainedafter the solvent was distilled off is recrystallized from methanol (500ml). In this way, the product is obtained in the form of palerose-colored crystals (98.1 g, 83%).

Melting point: 75-76° C.

TLC: Petroleum ether:ethyl acetate=3:1, Rf=0.75

¹H NMR (CDCl₃): δ 10.13 (s, 1H), 7.40 (s, 1H), 7.03 (s, 1H), 4.61(septet, J=6.4 Hz, 1H), 3.92 (s, 3H), 1.38 (d, J=6.4 Hz 6H);

¹³C NMR (CDCl₃): δ 190.8 (d), 15.6 (s), 147.1 (s), 126.4 (s), 120.0 (s),115.8 (d), 113.7 (d), 71.5 (d), 56.4 (q), 21.8 (q)

Step 2 2-Bromo-4-methoxy-5-(1-methylethoxy)benzenemethanol

2-Bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde (6.0 g, 22.0 mmol) isadded in substance at 15° C. within 15 minutes to a suspension of sodiumborohydride (1.67 g, 44.1 mmol) in anhydrous ethanol (60 ml), and themixture is stirred for one hour at room temperature.

The residue that remains after the solvent is distilled off is dispersedbetween saturated sodium bicarbonate solution (60 ml) and ether (100ml). The aqueous phase is extracted with ether (3×40 ml), the combinedorganic phases are washed with saturated sodium bicarbonate solution(1×100 ml), water (1×100 ml) and saturated common salt solution (1×100ml), dried (sodium sulfate/activated carbon) and filtered. After thesolvent is distilled off in a rotary evaporator, the product is obtainedin the form of colorless crystals (5.575 g, 95).

Melting point: 67-69° C.

TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.25

¹H NMR (CDCl₃): δ 7.00 (s, 2H), 4.64 (s, 2H), 4.50 (septet, J=6.4 Hz,1H), 3.85 (s, 3H), 2.05 (s, 1H), 1.34 (d, J=6.4 Hz, 6H);

¹³C NMR (CDCl₃): δ 150.1 (s), 146.5 (s), 131.8 (s), 116.1 (s), 115.9(d), 112.6 (s), 71.7 (t), 64.3 (d), 56.0 (q), 21.8 (q)

MT-44 JOS 1693

C₁₁H₁₅BrO₃ Cld.: C, 48.02; H, 5.50 Fnd.: C, 48.11; H, 5.29

Step 3 1-Bromo-2-(chloromethyl)-5-methoxy-4-(1-methylethoxy)-benzene

Thionyl chloride (20 ml) in absolute CH₂Cl₂ (10 ml) is added in dropswithin 10 minutes to 2-bromo-4-methoxy-5-(1-methylethoxy)benzenemethanol(5.63 g, 20.5 mmol) in absolute CH₂Cl₂ (60 ml), and it is stirred for 90minutes at room temperature.

The residue that is obtained after solvent is removed in a rotaryevaporator is dispersed between ether (100 ml) and saturated sodiumbicarbonate solution (100 ml), the combined organic phases are washedwith saturated sodium bicarbonate solution (2×100 ml), water (1×100 ml)and saturated common salt solution (1×100 ml), dried (sodiumsulfate/activated carbon), filtered, and the solvent is distilled off ina rotary evaporator. In this way, the product is obtained in the form ofcolorless crystals (5.72 g, 95%).

Melting point: 68-70° C.

TLC: Petroleum ether:ethyl acetate=3:1, Rf=0.9

¹H NMR (CDCl₃): δ 7.05 (s, 1H), 6.97 (s, 1H), 4.66 (s, 2H), 4.51(septet, J=6.4 Hz, 1H), 3.85 (s, 3H), 1.37 (d, J=6.4 Hz, 6H);

¹³C NMR (CDCl₃): δ 151.2 (s), 146.8 (s), 128.5 (s), 117.7 (s), 116.1(d), 114.8 (s), 71.9 (t), 56.2 (d), 64.4 (q), 21.9 (q)

MT-45 JOS 1760

C₁₄H₂₀O₃ Cld.: C, 71.16; H, 8.53 Fnd.: C, 70.90; H, 8.28

Step 4 1-[4-(1-Methylethoxy)phenyl]ethanone

1-(4-Hydroxyphenyl)ethanone (12.7 g, 93.2 mmol), 2-bromopropane (57.3 g,466 mmol) and potassium carbonate (62.2 g, 466 mmol, anhydrous, freshlyground) are stirred in absolute acetonitrile (150 ml) for 24 hours at60° C.

The reaction mixture is filtered, the solvent is distilled off in arotary evaporator, and the residue is dispersed between water (200 ml)and ether (200 ml). The aqueous phase is extracted with ether (2×80 ml),the combined organic phases are washed with water (2×100 ml) andsaturated common salt solution (1×100 ml), dried (sodiumsulfate/activated carbon) and filtered. In this way, after the solventis distilled off, the product is obtained in the form of colorlesscrystals (16.8 g, 99%).

Melting point: 36-80° C.

TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.5

¹H NMR (CDCl₃) δ 7.82 (d, J=9.5 Hz, 2H), 6.88 (d, J=9.5 Hz, 2H), 4.63(septet, J=6.4 Hz, 1H), 2.52 (s, 3H), 1.33 (d, J=6.4 Hz, 6H);

¹³C NMR (CDCl₃): δ 196.7 (s), 161.9 (s), 130.5 (d), 129.8 (s), 115.0(d), 70.0 (d), 26.2 (q), 21.8 (q)

Step 5 2-Bromo-1-[4-(1-methylethoxy)phenyl]ethanone

Bromine (11.7 g, 73.5 mmol) in absolute dioxane (70 ml)/absolute ether(100 ml) is added in drops within one hour to a solution of1-[(4-(1-methylethoxy)phenyl]ethanone (10.0 g, 56.0 mmol) in absolutedioxane (100 ml), and it is stirred for 2 hours at room temperature. Thereaction mixture is mixed with sodium sulfite (5.0 g) in water (100 ml),the phases are separated, and the aqueous phase is extracted with ether(3×100 ml), the combined organic phases are washed with water (2×100ml), saturated sodium bicarbonate solution (2×150 ml) and saturatedcommon salt solution (1×200 ml), dried (sodium sulfate/activatedcarbon), filtered, and the residue that is obtained after the solvent isdistilled off is crystallized under a mixture that consists of petroleumether (25 ml) and cyclohexane (25 ml) at −20° C. In this way, theproduct is obtained in the form of colorless crystals that rapidlybecome dark in color (8.80 g, 59%).

Melting point: 36-37° C.

TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.7

¹H NMR (CDCl₃): δ 7.93 (d, J=9.5 Hz, 2H), 6.92 (d, J=9.5 Hz, 2H), 4.63(septet, J=6.4 Hz, 1H), 4.40 (s, 2H), 1.35 (d, J=6.4 Hz, 6H);

¹³C NMR (CDCl₃) δ 189.8 (s), 162.7 (s), 131.4 (d), 126.4 (s), 115.3 (d),70.3 (d), 30.7 (t), 21.9 (q)

Step 6 1-(2-Bromoethyl)-4-(1-methylethoxy)benzene

Tert-butylamine-borane complex (7.45 g, 85.0 mmol, pellets or powder) isadded at 5° C. to a suspension of anhydrous aluminum chloride (5.70 g,43.0 mmol) in absolute CH₂Cl₂ (100 ml). After 15 minutes,2-bromo-1-[4-(1-methylethoxy)phenyl]-ethanone (7.30 g, 28.4 mmol) inanhydrous CH₂Cl₂ (50 ml) is added in drops within 30 minutes.

The mixture is stirred for three hours at room temperature, mixed with0.1N hydrochloric acid (100 ml), and the aqueous phase is extracted withCH₂Cl₂ (2×30 ml). The combined organic phases are washed with 0.1Nhydrochloric acid (2×50 ml), saturated sodium bicarbonate solution (2×50ml) and saturated common salt solution (1×100 ml), dried (sodiumsulfate/activated carbon), and the residue that is obtained after thesolvent is concentrated by evaporation is purified by bulb tubedistillation (0.05 mbar/80° C.), whereby the product is obtained as acolorless oil (5.81 g, 83%).

TLC: Petroleum ether, Rf=0.35

¹H NMR (CDCl₃): δ 7.18 (d, J=9.5 Hz, 2H), 6.87 (d, J=9.5 Hz, 2H), 4.53(septet, J=6.4 Hz, 1H), 3.53 (t, J=6.9 Hz, 2H), 3.08 (t, J=6.9 Hz, 2H),1.33 (d, J=6.4 Hz, 6H);

¹³C NMR (CDCl₃) δ 156.7 (s), 130.7 (s), 129.5 (d), 115.8 (d), 69.8 (d),38.5 (t), 33.2 (t), 21.9 (q)

MT-35 JOS 1760

C₁₁H₁₅BrO Cld.: C, 54.34; H, 6.22 Fnd.: C, 54.34; H, 6.09

Step 7 2-[2-[4-(1-Methylethoxy)phenyl]ethyl]propanedioic acid dimethylester

1-(2-Bromoethyl)-4-(1-methylethoxy)benzene (19.0 g, 78.1 mmol), malonicacid dimethyl ester (40.0 g, 300 mmol) and potassium carbonate (42.0 g,300 mmol, anhydrous, freshly ground) in absolute DMF (400 ml) arestirred for 10 hours at 70° C.

The solvent is removed in a rotary evaporator, and the residue isdispersed between water (250 ml) and ether (250 ml). The aqueous phaseis extracted with ether (1×100 ml), the combined organic phases arewashed with water (3×200 ml) and saturated common salt solution (1×150ml), dried (sodium sulfate/activated carbon) and excess malonic aciddimethyl ester is distilled off from the residue that is obtained afterthe solvent is removed from the rotary evaporator (160° C./15 mbar).

The crude product is purified by means of bulb tube distillation (140°C./0.001 mbar), by which the product is obtained as a colorless oil(18.9 g, 82%).

TLC: Petroleum ether:ethyl acetate=9:1, Rf=0.4

¹H NMR (CDCl₃): δ 7.08 (d, J=10 Hz, 2H), 6.81 (d, J=10 Hz, 2H), 4.50(septet, J=6.5 Hz, 1H), 3.71 (s, 6H), 3.32 (t, J=75 Hz, 1H), 2.58 (t,J=7.5 Hz, 2H), 2.19 (q, J=7.5 Hz, 2H), 2.65-2.47 (m, 2H), 2.26-2.06 (m,2H), 1.31 (d, J=6 Hz, 6H);

¹³C NMR (CDCl₃): δ 169.8 (s), 156.3 (s), 132.3 (s), 129.4 (d), 115.9(d), 69.9 (d), 52.5 (q), 50.8 (d), 32.4 (t), 30.6 (t), 22.1 (q)

Step 82-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl-2-[2-[4-(1-methylethoxy)phenyl]ethyl]propane-dioicacid methyl ester

2-[2[4-(1-Methylethoxy)phenyl]ethyl]propanedioic acid dimethyl ester(18.9 g, 64.2 mmol),1-bromo-2-(chloromethyl)-4-(1-methylethoxy)-5-methoxybenzene (18.9 g,64.2 mmol) and potassium carbonate (45.0 g, 32 l mmol, anhydrous,freshly ground) in absolute DMF (300 ml) are stirred for 12 hours at 60°C.

The residue that remains after the solvent is removed is dispersedbetween water (250 ml) and ether (250 ml). The aqueous phase isextracted with ether (1×100 ml), the combined organic phases are washedwith water (3×200 ml) and saturated common salt solution (150 ml), dried(sodium sulfate/activated carbon), filtered, and the solvent is removedin a rotary evaporator.

After drying under high vacuum, the product is obtained as a colorlessoil (33.7 g, 95%).

TLC: Petroleum ether:ethyl acetate=9:1, Rf=0.5

¹H NMR (CDCl₃): δ 7.04 (s, 1H), 7.01 (d, J=10 Hz, 2H), 6.79 (d, J=10 Hz,2H), 6.73 (s, 1H); 4.47 (septet, J=6.5 Hz, 1H), 4.36 (septet, J=6.5 Hz,1H), 3.80 (s, 3H), 3.72 (s, 6H) 3.48 (s, 2H), 2.65-2.47 (m, 2H),2.26-2.06 (m, 2H), 1.31 (d, J=6.5 Hz, 12H);

¹³C NMR (CDCl₃): δ 171.4 (s), 156.1 (s), 149.8 (s), 146.2 (s), 133.0(s), 129.3 (s), 129.1 (d), 118.2 (s), 116.2 (d), 116.0 (d), 115.8 (d),69.7 (d), 58.7 (s), 55.9 (q), 52.3 (q), 37.4 (t), 34.5 (t), 29.9 (t),21.95 (q), 21.9 (q)

MT-54 JOS 1698

C₂₇H₃₅BrO₇ Cld.: C, 58.81; H, 6.40 Fnd.: C, 59.00; H, 6.26

Step 9Alpha-[[2-bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-4-(1-methylethoxy)benzenebutanoicacid

2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl-2-(2-[4-(1-methylethoxy)-phenyl]ethyl]propanedioicacid dimethyl ester (33.7 g, 61.1 mmol) and potassium hydroxide (17.5 g,312 mmol) are stirred in ethanol (150 ml)/water (30 ml) for 12 hours atboiling temperature.

The reaction mixture is acidified with concentrated hydrochloric acid upto a pH of 1 and kept under reflux for one hour.

The residue that remains after the solvent is removed is dispersedbetween water (250 ml) and ether (250 ml). The aqueous phase isextracted with ether (2×100 ml), the combined organic phases are washedneutral with water, washed with saturated common salt solution (150 ml),dried (sodium sulfate/activated carbon) and filtered. The residue thatremains after the solvent is removed is decarboxylated in a bulb tubefor 30 minutes at 140° C. and then distilled at 150° C./0.005 mbar. Inthis way, the product is obtained in the form of colorless crystals(27.5 g, 94%).

Melting point: 114-116° C.

TLC: Chloroform:methanol=9:1, Rf=0.65

¹H NMR (DMSO-d₆): δ 7.09, (s, 1H), 7.01 (d, J=7.3 Hz, 2H), 6.80 (s, 1H),6.78 (d, J=7.3 Hz, 2H), 4.69-4.37 (m, 2H), 372 (s, 3H), 3.00-2.33 (m,5H), 1.99-1.58 (m, 2II), 1.18 (d, J=6.4 Hz, 12H);

¹³C NMR (DMSO₆) 176.0 (s), 155.6 (s), 149.3 (s), 145.8 (s), 133.1 (s),130.3 (s), 129.1 (d), 118.1 (d), 116.0 (d), 115.5 (s), 114.1 (d), 70.6(d), 69.0 (d), 55.8 (q), 44.9 (d), 33.5 (t), 31.9 (t), 21.85 (q), 21.8(q)

MT-100 JOS 1592

C₂₄H₃₁BrO₅ Cld.: C, 60.13; H, 6.52 Fnd.: C, 60.38; H, 6.55

Step 10 Alpha[[2-bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-4-(1-methylethoxy)benzenebutanoicacid amide

Thionyl chloride (50 ml) is added in drops at 0° C. within 15 minutes toalpha[[2-bromo-4-methoxy-5-(1-methylethoxy)phenyl]methyl]-4-(1-methylethoxy)-benzenebutanoicacid (10.0 g, 20.8 mmol) in CH₂Cl₂ (100 ml), and the mixture is stirredfor two hours at this temperature.

The solvent is removed in a rotary evaporator, the residue is taken upin absolute formamide (15 ml) and mixed at 0° C. with ammonia informamide (100 ml of a solution that is saturated at this temperature).The mixture is stirred for one hour at 0° C. and poured onto water (1500ml).

The precipitated crystals are filtered off and digested with water(4×400 ml). In this way, the product is obtained in the form ofcolorless crystals (9.21 g, 92%).

Melting point: 154-156° C.

TLC: CH₂Cl₂:methanol=9:1, Rf=0.7

¹H NMR (DMSO-d₆): δ 7.32 (s, 1H), 7.08 (s, 1H), 7.02 (d, J=7.3 Hz, 2H),6.83 (s, 1H), 6.80 (s, 1H), 6.78 (d, J=7.3 Hz, 2H), 4.68-4.32 (m, 2H),3.77 (s, 3H), 3.39 (s, 3H), 3.00-2.62 (m, 2H), 2.00-1.58 (m, 2H), 1.18(d, J=6.4 Hz, 12H);

¹³C NMR (DMSO-d₆): 175.8 (s), 155.5 (s), 149.1 (s), 145.8 (s), 133.5(s), 130.9 (s), 129.9 (d), 118.1 (d), 115.8 (d), 115.5 (s), 114.1 (d),70.9 (d), 69.0 (d), 55.8 (q), 45.9 (d), 34.2 (t), 32.1 (t), 21.85 (q),21.8 (q)

MT-112 JOS 1591

C₂₄H₃₂BrNO₄ Cld.: C, 60.25; H, 6.74; N, 2.93 Fnd.: C, 59.99; H, 6.56; N,2.82

Step 11 Production ofalpha[[2-bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoicacid amide

Boron trichloride (40 ml, 1.6 M in CH₂Cl₂) is added in drops at −78° C.to a solution ofalpha[[2-bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoicacid amide (9.30 g, 19.4 mmol) in absolute CH₂Cl₂ (150 ml), and it isstirred for one hour at this temperature. Then, the mixture is heated toroom temperature and stirred for two hours.

It is mixed with water (300 ml), and the organic solvent is distilledoff in a rotary evaporator, whereby the crude product precipitates ascrystals, the latter is filtered off and is digested with water (6×200ml) and diisopropyl ether (2×40 ml). In this case, the product isobtained in the form of colorless crystals (6.76 g, 88%).

Melting point: 177-179° C.

TLC: CH₂Cl₂:methanol=9:1, Rf=0.4

¹H NMR (DMSO-d₆): δ 9.18 (s, 2H), 7.18 (S, III), 7.04 (s, 1H), 6.97 (d,J=7.3 Hz, 2H), 6.72 (s, 1H), 6.65 (s, 1H), 6.66 (d, J=7.3 Hz, 2H), 3.77(s, 3H), 3.48 (s, 3H), 2.92-2.38 (m, 4H);

¹³C NMR (DMSO-d₆): δ 175.6 (s), 155.5 (s), 147.0 (s), 145.8 (s), 131.3(s), 129.9 (s), 129.8 (d), 117.9 (s), 115.8 (d), 115.0 (d), 11.9 (d),56.0 (q), 48.1 (d), 37.6 (t), 37.0 (t)

MT-114 JOS 1692

C₁₈H₂₀BrO₄ Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.55; H, 4.90; N,3.28

Step 121-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi]benzofuran-11-carboxylicacid amide

α-[[2-Bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoicacid amide (3.00 g, 7.61 mmol) is suspended in chloroform (300 ml) andmixed with a solution of potassium hexacyanoferrate (III) (13.2 g, 40.0mmol) in potassium carbonate solution (75 ml, ten percent).

The mixture is stirred vigorously at room temperature for 40 minutes andfiltered on Hyflo. The aqueous phase is extracted with chloroform (3×50ml), the combined organic phases are washed with water (2×200 ml) andsaturated common salt solution (1×150 ml), dried (sodium sulfate/silicagel), filtered, and the crude product that is obtained after the solventis concentrated by evaporation is purified by column chromatography (50g of silica gel, ethyl acetate). In this way, the product is obtained inthe form of colorless crystals (0.36 g, 12%).

TLC: Chloroform:methanol 9:1, Rf=0.4 and 0.5

¹H NMR (CDCl₃): δ 7.00 (s, 1H); 6.86 (dd, J=12 Hz, J=1 Hz, 1H), 6.06 (d,J=1 Hz, 1H), 5.02 (bs, 2H), 4.70 (s, 1H), 3.82 (s, 3H), 3.62 (d, J=16Hz, 1H), 3.23 (dd, J=16 Hz, J=3 Hz, 1H), 3.08-2.89 (m, 1H), 2.77 (dd,J=16 Hz, J=6 Hz, 1H), 2.62-1.70 (m, 5H)

¹³C NMR (DMSO-d₆): δ 202.5 (s), 184.9 and 179.1 (s), 146.5 and 146.1(d), 145.0 and 145.9 (s), 143.3 and 142.0 (s), 132.0 and 131.8 (s),128.9 and 128.0 (s), 126.7 and 126.2 (d), 116.3 and 115.0 (s), 114.4(d), 87.4 and 87.3 (d), 56.0 (q), 49.5 and 49.3 (s), 45.3 (d), 37.3 and37.0 (t), 35.4 (t), 34.4 (t), 30.4 (t)

Deeper-Running Diastereomer

¹H NMR (CDCl₃) δ 6.70-6.85 (m, 2H), 6.07-5.91 (m, 2H), 4.54 (s, 1H),4.12 (s, 1H), 3.82 (s, 3H), 2.99 (s, 1H), 2.86 (t, J=15 Hz, 1H), 2.72(d, J=16 Hz, 1H), 2.63 (dd, J=16 Hz, J=3 Hz, 1H), 2.30-1.60 (m, 9H);

¹³C NMR (CDCl₃): δ 146.4 (s), 143.9 (s), 133.7 (s), 128.5 (s), 128.1(d), 127.5 (d), 123.3 (d), 111.7 (d), 88.9 (d), 62.4 (d), 56.3 (q), 52.8(d), 48.3 (s), 45.1 (t), 35.8 (t), 35.6 (t), 30.4 (t)

MT-115 JOS 1585

C₁₈H₁₈BrNO₄ Cld.: C, 55.12; H, 4.63; N, 3.57 Fnd.: C, 54.91; H, 4.66; N,3.41

EXAMPLE 811-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-11-carboxylicacid amide

L-Selectride® (6.6 ml, 6.6 mmol, 1 M in THF) is added at 0° C. within 15minutes to a suspension of1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi]benzofuran-11-carboxylicacid amide (860 mg, 2.19 mmol) in absolute THF (5 ml), and the mixtureis stirred for 12 hours at room temperature. It is hydrolyzed with water(3 ml) and dispersed between water (10 ml) and ethyl acetate (10 ml),the aqueous phase is extracted with ethyl acetate (3×5 ml), the combinedorganic phases are washed with 1N hydrochloric acid (3×10 ml), water(2×10 ml), saturated sodium bicarbonate solution (1×10 ml) and saturatedcommon salt solution (1×10 ml), dried (sodium sulfate/activated carbon),filtered, and the crude product that is obtained after the solvent isdistilled off is purified by column chromatography (50 g of silica gel,ethyl acetate). In this way, the product is obtained in the form ofcolorless crystals (741 mg, 86%).

TLC: Chloroform:methanol=9:1, Rf=0.35 and 0.45

¹H NMR (CDCl₃): δ 6.92 (s, 1H), 6.10-5.89 (m, 2H), 5.82-5.53 (m, 2H),4.54 (s, 1H), 4.13 (s, 1H), 3.81 (s, 3H), 3.51 (d, J=15 Hz, 1H), 3.05(dd, J=17 Hz, J=6 Hz, 1H), 2.96-2.84 (m, 1H), 2.65 (d, J=16 Hz, 1H),2.83 (dd, J=16 Hz, J=6 Hz, 1H), 2.44-1.40 (m, 9H);

¹³C NMR (CDCl₃): δ177.7 and 175.2 (s), 145.3 (s), 145.7 (s), 144.2 (s),and 143.9 (s), 133.8 and 134.2 (s), 128.3 and 128.2 (d), 126.5 (d),116.1 and 115.9 (s), 115.3 and 115.1 (d), 88.5 (d), 61.8 (d), 56.1 (q),49.1 and 49.0 (s), 46.0 (d), 41.9 (t), 35.9 and 35.7 (t), 29.8 and 29.6(t), 28.8 and 26.2 (t)

MT-120

JOS 1710

C₁₈H₂₀BrNO₄ Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.84; H, 5.18; N,3.43

EXAMPLE 8211-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzo-furan-6-ol(SPH-1459)

Bis(trifluoroacetoxy)iodobenzene (PIFA, 787 mg, 1.78 mmol) is dissolvedin acetonitrile (3.5 ml, HPLC-quality) and mixed with water (3.5 ml,HPLC-quality). Then,1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-11-carboxylicacid amide is added in substance within 2 hours, and the mixture isstirred for 24 hours at room temperature. The solvent is distilled offin a rotary evaporator, the residue is taken up in chloroform (5 ml),filtered, and purified by column chromatography (30 g of silica gel,chloroform:methanol: ammonia=96:3:1). In this way, the product isobtained in the form of colorless crystals (490 mg, 75%)

TLC: Chloroform:methanol=9:1, Rf=0.2 and 0.25

¹H NMR (MeOH-d₄) δ 7.07 (s, 1H), 6.12-5.87 (m, 2H), 5.82-5.53 (m, 2H),4.53 (s, 1H), 4.14 (s, 1H), 3.80 (s, 3H), 3.59 (d, J=20 Hz, 1H),3.14-2.92 (m, 1H), 2.47 (d, J=17 Hz, 1H), 2.16 (s, 3H), 2.01-2.62 (m,2H);

¹³C NMR (MeOH-d₄): δ 148.3 and 148.2 (s), 146.5 and 146.1 (s), 135.8(s), 129.9 and 129.3 (s), 128.5 and 127.9 (d), 125.9 and 123.9 (d),118.4 and 118.1 (s), 116.9 and 116.0 (d), 118.4 and 118.0 (s), 116.8 and116.0 (d), 89.0 and 88.9 (d), 62.4 and 62.3 (d), 57.2 (q), 50.6 and 50.4(s), 49.8 (d), 38.5 (t), 36.0 and 33.0 (t), 31.8 and 31.0 (t), 31.4 and2.8.3 (t)

JOS 1707

C₁₇H₂₀BrNO₃*1 CHCl₃ Cld.: C, 44.52; H, 4.36; N, 2.88 Fnd.: C, 44.90; H,4.30; N, 2.67

EXAMPLE 8311-Amino-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[[a]cyclohepta[hi]benzofuran-6-ol

Production of the Copper-Zinc Alloy

Zinc powder (600 mg) and copper(I) iodide are reacted under argon inwater (4 ml) and ethanol (4 ml) for 45 minutes in an ultrasonic bath,whereby a dark-black, fine-powder suspension is produced.

Debromination

11-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol(80 mg, 0.22 mmol) and calcium chloride (300 mg, 2.7 mmol) are added insubstance to the suspension that is produced, and the mixture is stirredfor 12 hours at boiling temperature. It is mixed with concentratedaqueous ammonia solution (1 ml), the solvent is removed in a rotaryevaporator, the residue is taken up in chloroform (15 ml), filtered, andthe residue that is obtained after the filtrate is concentrated byevaporation in a rotary evaporator is purified by column chromatography(30 g of silica gel, chloroform:methanol:ammonia=96:3:1). In this way,the two optical isomers can be separated (10 mg, 0.04 mmol of isomer A:26 mg, 0.09 mmol of isomer B; a total of 36 mg, 59%) and obtained as acolorless foam.

Higher-Running Diastereomer

¹H NMR (CDCl₃): δ 6.73-6.62 (m, 2H), 6.05 (s, 2H), 4.62 (s, 1H), 4.14(s, 1H), 3.82 (s, 3H), 3.57 (s, 1H), 3.22 (d, J=16 Hz, 1H), 2.83 (dd,J=16 Hz, J=6.5 Hz, 1H), 2.24-1.60 (m, 9H);

¹³C NMR (CDCl₃): δ 146.2 (s), 144.3 (s), 133.6 (s), 128.4 (s), 128.1(d), 127.2 (d), 124.8 (d), 111.9 (d), 89.0 (d), 62.6 (d), 56.3 (q) 49.0(s), 48.3 (d), 41.8 (t), 32.5 (t), 30.4 (t), 30.4 (t)

Deeper-Running Diastereomer

¹H NMR (CDCl₃): δ 6.70-6.58 (m, 2H), 6.07-591 (m, 2H), 4.54 (s, 1H),4.12 (s, 1H), 3.82 (s, 3H), 2.99 (s, 1H), 2.86 (t, J=15 Hz, 1H), 2.72(d, J=16 Hz, 1H), 2.63 (dd, J=16 Hz, J=3 Hz, 1H), 2.30-1.60 (m, 9H);

¹³C NMR (CDCl₃): δ 146.4 (s), 143.9 (s), 133.7 (s), 128.5 (s), 128.1(d), 127.5 (d), 123.3 (d), 111.7 (d), 88.9 (d), 62.4 (d), 56.3 (q), 52.8(d), 48.3 (s), 45.1 (t), 35.8 (t), 35.6 (t), 30.4 (t).

EXAMPLE 84 Step 1 Condensation and Reduction: General OperatingInstructions

  1 equivalent 2-methyl-4-methoxy-5-hydroxybenzaldehyde or2,4-dimethoxy-5-hydroxybenzaldehyde   1 equivalent tyramine 0.8equivalent sodium borohydride  10 ml ethanol (96%)/1 g of aldehyde

The educt was suspended in ethanol, and the tyramine was added whilebeing stirred, then the reaction mixture was refluxed for 8.5 hours.Since the Schiff base (MH-16′ or 34′) that formed on the TLC platebreaks back down into the starting materials, the reaction progress wasdetermined by reduction of a small sample with sodium borohydride,conventional working-up and application of the product obtained.

After 8.5 hours, the reaction mixture was cooled in an ice bath to 0°C., and the sodium borohydride, dissolved in 4 ml of water/1 g, wasslowly added in drops, then stirred in an ice bath for 30 minutes. Then,it was poured onto 150 ml of ice/water/1 g of aldehyde while beingstirred vigorously, the white precipitate that was produced was filteredoff and dried in a vacuum drying oven. A second fraction of the product,which was collected and dried, was precipitated from the mother liquor.

EXAMPLE 84 Step 1a;5-(N-[2-[4-Hydroxyphenyl]ethyl]aminomethyl)-2-methoxy-4-methylphenol(MH-16)

27.8 g (168 mmol) 2-methyl-4-methoxy-5- hydroxybenzaldehyde (6) 23.0 g(168 mmol) tyramine 5.20 g (134 mmol) = sodium borohydride  0.8equivalents

Yield: 43.4 g (161 mmol=96% of theory) of a beige powder C₁₇H₂₁NO₃[287.36]

TLC: R_(f)=0.21 (CHCl₃:MeOH=9:1+1% concentrated NH₄OH)

Melting point: 122-124° C. % C % H % N Cld.: 71.06 7.37 4.87 Fnd.: 71.077.41 4.86

¹H-NMR (200 MHz, DMSO-d₆): δ 6.90 (m, 2H), 6.67 (s, 1H), 6.62 (m, 2H),6.55 (s, 1H); 3.72 (s, 3H); 3.51 (s, 2H); 2.73 (t, J=6.5 Hz, 2H); 2.60(t, J=6.5 Hz, 2H); 2.10 (s, 3H); ¹³C-NMR (50 MHz, DMSO-D₆): δ 155.4 (s),145.8 (s), 143.9 (s), 130.9 (s), 130.4 (s), 129.3 (d), 126.0 (s), 116.2(d), 115.0 (d), 114.3 (d), 55.7 (q), 51.1 (t), 50.3 (t), 35.0 (t), 17.9(q)

EXAMPLE 84 Step 1b5-(N-[2-[4-Hydroxyphenyl]ethyl]aminomethyl)-2,4-dimethoxyphenol (MH-34)

18.85 g (103.47 mmol) 5-hydroxy-2,4-dimethoxy- benzaldehyde (8) 14.21 g(103.47 mmol) tyramine  3.13 g (82.74 mmol) = NaBH₄  0.8 equivalent  200ml ethanol 96%

Yield: 28.1 g 92.63 mmol=89.5% of theory

C₁₇H₂₁NO₄ [303.36]

TLC: R_(f)=0.14 (CHCl₃:MeOH=9:1+1% concentrated NH₄OH)

Melting point: 170-173° C.

C₁₇H₂₁NO₄ [303.36] (contaminated with aliphatic substance about C₁₅H₃₂,Schliffett) % C % H % N Cld.: 67.31 6.98 4.62 Fnd.: 68.10 7.04 4.66

¹H-NMR (200 MHz, DMSO-d₆): δ 6.95 (m, 2H), 6.70 (s, 1H) 6.64 (m, 2H),6.57 (s, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 3.52 (s, 2H), 2.59 (bs,4H);”³C-NMR (50 MHz, DMSO-d₆): δ 155.3 (s), 149.9 (s), 146.3 (s), 139.7(s), 130.4 (s), 129.3 (d), 120.4 (s), 116.6 (d), 115.0 (d), 98.4 (d),56.0 (q+q), 50.6 (t), 47.1 (t), 35.0 (t)

EXAMPLE 84 Step 2 Formylation: General Operating Instructions

  1 equivalent amine   2 equivalents formic acid ester (ethyl formate ormethyl formate)  10 ml 1,4-dioxane, distilled/1 g of amine 0.2 mldimethylformamide/1 g of amine

Catalytic Amount of Formic Acid

All reagents were refluxed together (formic acid optionally was addedseveral times), and the reaction mixture was evaporated to the dry statein a vacuum after the end of the reaction. The solid residue was takenup in 10 ml of methanol/1 g of amine, and 50 ml of ice/water/1 g ofamine was added in portions while being stirred, whereby the suspensionof the intermediate product was converted under hydrolysis into theflocculent end product, which was suctioned off and dried.

EXAMPLE 84 Step 2aN-((5-Hydroxy-4-methoxy-2-phenylmethyl)-N-(2-[4-hydroxyphenyl]ethyl)]formamide(MH-18)

55.0 g (191 mmol) 5-(N-[2-[4- hydroxyphenyl]ethyl]aminomethyl)-2-methoxy-4-methylphenol (XVII) 23.5 ml (383 mmol = methyl formate   2equivalents) 11.0 ml DMF 1.50 ml formic acid  400 ml 1,4-dioxane.

The working-up is carried out after 7 hours.

Yield: 49.8 g (158 mmol=82.6% of theory) of a beige powder

C₁₈H₂₁NO₄ [315.37]

TLC: R_(f)=0.35 (CHCl₃:MeOH=9:1+1% concentrated NH₄OH)

Melting point: 170-171° C. % C % H % N Cld.: 68.55 6.71 4.44 Fnd.: 68.776.86 4.14

¹H-NMR (200 MHz, DMSO-d₆): δ 9.20 (s, 1H), 8.74 (d, J=15.3 Hz, 1H), 8.19(s, 0.5H),7.88 (s, 0.5H), 7.00-6.87 (m, 2H), 6.74 (s, 1H), 6.72-6.56 (m,2H), 6.59 (s, 1H), 4.31 (s, 1H), 4.23 (s, 1H), 3.73 (s, 3H), 3.21 (dd,J=15.3, 7.6 Hz, 2H), 2.60 (t, J=7.6 Hz, 2H), 2.12 (s, 3H); ¹³C-NMR (50MHz, DMSO-d₆) δ 162.7 and 162.3 (d), 155.7 (s), 146.7 and 146.5 (s),144.4 and 144.2 (s), 129.7 and 129.4 (d), 128.9 and 128.4 (s), 126.5(s), 126.4 and 126.3 (s), 116.3 and 115.9 (d), 115.1 (d), 114.6 and114.4 (d), 55.6 (q), 48.0 and 47.4 (t), 43.3 and 41.6 (t), 33.2 and 31.9(t), 18.1 and 18.0 (q).

EXAMPLE 84 Step 2b

N-(2-(4-Hydroxyphenyl)ethyl)-N-((5-hydroxy-2,4-dimethoxyphenyl)methyl)-formamide(MH-35)

  27 g (89 mmol) 5-(N-[2-[4- hydroxyphenyl]ethyl]aminomethyl)-2,4-dimethoxyphenol (XXV) 14.4 ml (178 mmol) ethyl formate  200 ml1,4-dioxane  5.5 ml dimethylformamide   2 ml formic acid

The working-up was carried out after 24 hours, and the formic acid wasadded in 3 portions at intervals of several hours.

Yield: 26.13 g (78.85 mmol=88.6% of theory) of a beige powder

C₁₈H₂₁NO₅ [331.37]

TLC: R_(f)=0.53 (CHCl₃:MeOH=9:1+1% concentrated NH₄OH)

Melting point: 130-132° C. % C % H % N Cld.: 65.24 6.39 4.23 Fnd.: 64.976.40 4.18

¹H-NMR (200 MHz, DMSO-d₆): δ 9.18 (bs, 1H), 8.48 (d, J=7.4 Hz, 1H), 8.16(s, 0.5H), 7.86 (s, 0.5H), 6.98-6.87 (m, 2H), 6.71-6.58 (m, 4H), 4.31(s, 1H), 4.19 (s, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.21 (dd, J=16.4, 7.7Hz, 2H), 2.69-2.55 (m, 2H); ¹³C-NMR (50 MHz, DMSO-d₆): δ 162.7 and 162.5(d), 155.7 and 155.6 (s), 150.6 and 150.3 (s), 146.7 and 147.3 (s),140.1 and 139.9 (s), 129.6 and 129.3 (d), 129.0 and 128.4 (s), 116.8 and116.4 (d), 116.2 and 115.9 (s), 115.1 (d), 98.5 and 98.4 (d), 56.3 and56.2 (q), 55.9 (q), 47.9 and 45.2 (t), 43.0 and 38.3 (t), 33.4 and 31.9(t)

EXAMPLE 84 Step 3 Phenolic Oxidative Coupling: 1-Methylgalanthamine (XV)

[(±)-(4aα,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-6-oxo-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-carboxaldehyde,1-Methyl-N-formylnarwedine (MH-19)

11.4 g (69.8 mmol) N-((5-hydroxy-4-methoxy-2- phenylmethyl)-N-(2-[4-hydroxyphenyl]ethyl]formamide (XVIII) 47.0 g (338 mmol) potassiumcarbonate 47.0 g (142 mmol) potassium hexacyanoferrate (III) 1.60 ltoluene 470 ml water 40.0 g Hyflo

Potassium carbonate, potassium hexacyanoferrate (III), water and toluenewere heated in a 4 liter-four-neck flask to 80° C., and then the eductwas sprinkled while being mechanically stirred vigorously. Thetemperature was kept at 80° C. for 1 hour, then Hyflo was added andstirred for 10 more minutes. The reaction mixture was suctioned off, andthe solid residue was rewashed 1× with water and 3× with hot toluene.The toluene phase was separated from the aqueous phase, and the latterwas extracted with toluene. The organic phases were combined, thesolvent was drawn off, and the product was dried in a vacuum dryingoven.

Yield: 6.17 g (19.7 mmol=55.0% of theory) of a light yellow powder

C₁₈H₁₉NO₄ [313.39]

TLC: R_(f)=0.48 and 0.42 (2 rotamers) (CHCl₃:MeOH=9:1+1% concentratedNH₄OH)

Melting point: Decomposition>215° C. % C % H % N Cld.: 69.00 6.11 4.47Fnd.: 68.78 6.33 4.40

¹H-NMR (Mixture that consists of 2 rotamers, 200 MHz, DMSO-d₆): δ 8.18(s, 0.2H), 8.10 (s, 0.8H), 7.25 (dd, J=10.4, 1.9 Hz, 0.8H), 7.15 (dd,J=10.4, 1.9 Hz, 0.2H), 6.73 (s, 0.2H), 6.69 (s, 0.8H), 5.95 (d, J=10.3Hz, 0.8H), 5.93 (d, J=10.3 Hz, 0.2H), 5.14 (d, J=15.4 Hz, 0.8H), 4.83(d, J=15.4 Hz, 0.2H), 4.67 (bs, 1H), 4.51 (d, J=15.4 Hz, 0.2H), 4.07 (d,J=15.4 Hz, 0.8H), 3.97 (bs, 1H), 3.78-3.60 (m, 4H), 3.07 (dd, J=17.4,3.4 Hz, 1H), 2.78 (dd, J=17.4, 1.9 Hz, 1H), 2.33 (s, 3H), 2.30 (s,0.8H), 2.22 (s, 0.2H), 1.86 (dt, J=13.5, 3.7 Hz, 1H) ¹³C-NMR (mixturethat consists of 2 rotamers, 50 MHz, DMSO-d₆): δ 194.9 (s), 162.8 and162.1 (d), 145.2 and 144.8 (d), 145.5 and 145.3 (s), 142.9 and 142.8(s), 130.6 and 130.3 (s), 128.2 (s), 127.5 and 127.0 (s), 126.4 and126.2 (d), 114.5 and 114.2 (d), 87.0 and 86.8 (d), 55.6 (q), 49.2 and49.0 (s), 47.4 and 45.6 (t), 41.8 and 40.1 (t), 37.7 (t), 37.5 (t), 37.4(t), 34.1 (t), 19.2 and 18.9 (q)

EXAMPLE 85[(±)-(4aα,6β,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methyl-N-demethylgalanthamine (MH-20)

500 mg (1.60 mmol) 1-Methyl-N-formylnarwedine (XIX) 6.00 ml (6.06 mmol =L-selectride 1 M in THF 3.78 equivalents) 12.0 ml absolute THF

A suspension of finely ground educt in absolute THF was cooled to 0° C.,and then L-selectride was added in drops, whereby a temperature increaseof 5° C. was to be observed. At 0° C., it was stirred for 1 hour,whereby a clear solution formed. After 70 minutes, 5 drops of water and1 ml of concentrated aqueous ammonia were added, stirred for 10 minutes,and then the reaction mixture was concentrated by evaporation by 50% ina vacuum. Then, 10 ml of ammonia were added once more, and the solutionwas extracted with methylene chloride. The combined organic phases wererewashed once with dilute ammonia solution, dried on sodium sulfate,filtered, and the solvent was drawn off. The luminous red oil that wasproduced was purified on a silica gel column.

Yield: 440 mg (1.53 mmol=96.0% of theory) of a colorless oil

C₁₇H₂₁NO₃ [287.36]

TLC: R_(f)=0.39 (CHCL₃:MeOH=9:1+1% NH₄OH)

C₁₇H₂₁NO₃×0.8 H₂O [301.76] % C % H % N Cld.: 67.66 7.55 4.64 Fnd.: 67.607.40 4.65

¹H-NMR (200 MHz, CDCl₃): δ 6.51 (s, 1H), 6.06 (d, J=10.2 Hz, 1H), 5.97(dd, J=10.2, 4.5 Hz, 1H), 4.57 (bs, 1H), 4.27 (d, J=16.0 Hz, 1H), 4.11(t, J=4.4 Hz, 1H), 3.80 (s, 3H), 3.77 (d, J=16.0 Hz, 1H), 3.40-3.10 (m,2H), 2.65 (dd, J=15.6, 3.2 Hz, 1H), 2.23 (s, 3H), 1.99 (ddd, J=15.6,4.9, 2.3 Hz, 1H), 1.89-1.63 (m, 2H); ¹³C-NMR (50 MHz, CDCl₃): δ 144.4(s), 142.9 (s), 133.4 (S), 130.5 (s), 127.8 (s), 127.5 (d), 127.1 (d),113.5 (d), 88.1 (d), 61.4 (d), 55.8 (q), 49.0 (s), 48.9 (t), 46.9 (t)39.7 (t), 29.8 (t), 19.4 (q)

EXAMPLE 86[(±)-(4aα,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,4′-dimethyl-spiro[-6H-benzofuro[3a,3,2-ef][2]benzazepine]-6,2′-[1,3]-dioxolane]-11-carboxaldehyde,1-methyl-N-formyl-narwedine ketal (MH-21)

6.17 g (19.7 mmol) 1-methyl-N-formylnarwedine (XIX) 40.0 ml toluene 375mg (1.97 mmol) p-toluenesulfonic acid 11.1 ml (149 mmol) propyleneglycol

In a flask with a water separator, the educt was introduced intotoluene, and ⅓ of the p-toluenesulfonic acid was added to ⅔ of propyleneglycol. The reaction mixture was refluxed, and after 2 hours, thesolution of the residual p-toluenesulfonic acid in propylene glycol wasadded in portions over 5 hours, then refluxed for another 6 hours. Afterthe end of the reaction (HPLC study necessary, since TLC has littleinformational value), the toluene phase was separated, and the propyleneglycol phase was exhaustively extracted with toluene. The collectedtoluene phases were extracted 2× with acetic acid (8% in water), 2× withsaturated sodium bicarbonate solution and 2× with water, then thesolvent was drawn off.

Yield: 5.34 g (14.38 mmol=73% of theory) of a beige foam

C₂₁H₂NO₅ [371.44]

TLC: R_(f)=0.71 (CHCl₃:MeOH=9:1)

C₂₁H₂₅NO₅×0.85 H₂O [386.74] % C % H % N Cld.: 65.22 6.96 3.62 Fnd.:65.39 7.19 3.52

¹H-NMR (mixture that consists of diastereomers and rotamers, 200 MHz,CDCl₃): δ 8.14-8.01 (m, 1H), 7.30-7.09 (m, 2H), 6.51 (s, 1H), 6.22-5.97(m, 1H), 5.85-5.61 (m, 1H), 5.38 and 4.77 (d, J=15.7 Hz, 1H), 4.49 (bs,1H), 4.37-4.01 (m, 2H), 3.93-3.74 (m, 5H), 3.71-3.10 (m, 1H), 2.79-2.58(m, 1H), 2.41 (s, 2H), 2.32 (d, J=10.2 Hz, 3H), 2.25-1.74 (m, 3H);¹³C-NMR (mixture that consists of diastereomers and rotamers, 50 MHz,CDCl₃): δ 162.5 (d), 161.7 (d), 143.7 (s), 143.6 (s), 143.3 (d), 142.7(d), 129.9 (s), 129.6 (s), 127.8 (d), 127.6 (d), 126.0 (s), 125.7 (s),114.6 (d), 114.4 (d), 87.5 (d), 87.4 (d), 68.2 (d), 68.0 (t), 56.1 (q),56.0 (q), 49.2 (s), 49.0 (s), 48.7 (t), 46.7 (t), 43.2 (t), 41.2 (t),38.7 (t), 37.2 (t), 37.1 (t), 34.8 (t), 19.7 (q), 19.4 (q), 18.9 (q)

EXAMPLE 87[(±)-(4aα,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-one,1-methylnarwedine (MH-22)

5.34 g (14.4 mmol) 1-methyl-N-formylnarwedine ketal (XX) 25.2 ml (25.2mmol) = lithium aluminum hydride 1 M in THF 1.75 equivalents 20 mlabsolute THF

1-Methyl-N-formylnarwedine (V) was dissolved in absolute THF, andlithium aluminum hydride was added in portions while being stirred.After 15 minutes, the reaction mixture was mixed with 10 ml of toluene,then hydrolyzed with 1.5 ml of water, and after 1.5 ml of sodiumhydroxide solution (15% in water) was added, it was stirred for 15minutes. After 1.5 g of Hyflo was added, it was refluxed for 1 hour,filtered off, the filter cake was boiled up 3× with 10 ml oftoluene:THF=1:1 each and in each case suctioned off. The organic phaseswere evaporated to the dry state, taken up with 25 ml of 4N HCl andstirred for 25 minutes at 60° C., then exhaustively extracted with ethylacetate. The collected organic phases were backwashed with dilute HCl.The collected acidic, aqueous phases were released by distillation ofexcess ethyl acetate, then made basic with concentrated aqueous ammoniaand exhaustively extracted with chloroform. The collected chloroformphases were washed with saturated common salt solution, dried on sodiumsulfate, filtered, and the solvent was drawn off. The purification wascarried out by recrystallization from diisopropyl ether:ethylacetate=9:1.

Yield: 4.01 g (13.36 mmol=93% of theory) of light yellow, very fineneedles

C₁₈H₂₁NO₃ [299.37]

TLC: R_(f)=0.42 (CHCl₃:MeOH 95:5)

Melting point: 121-122° C. % C % H % N Cld.: 72.22 7.07 4.68 Fnd.: 71.957.08 4.57

¹H-NMR (200 MHz, CDCl₃): δ 7.01 (dd, J=10.4, 1.6 Hz, 1H), 6.56 (s, 1H),5.99 (d, J=10.4 Hz, 1H), 4.68-4.62 (m, 1H), 3.97 (d, J=15.7 Hz, 1H),3.80 (s, 3H), 3.79 (d, J=15.7 Hz, 1H), 3.22-2.95 (m, 3H), 2.71 (dd,J=17.8, 3.7 Hz, 1H), 2.44 (s, 3H), 2.23 (s, 3H), 2.20-2.01 (m, 1H), 1.87(dt, J=13.8, 3.4 Hz, 1H) ¹³C-NMR (50 MHz, CDCl₃): δ 194.4 (s), 145.2(s), 142.9 (s), 131.0 (s), 128.9 (s), 126.8 (d+d+s), 114.3 (d), 87.7(d), 55.9 (q), 55.8 (t), 54.1 (t), 48.9 (s), 43.5 (q), 37.1 (t), 33.4(t), 19.4 (q)

EXAMPLE 88[(±)-(4aα,6β,8aR)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methylgalanthamine (MH-30)

170 mg (0.57 mmol) 1-methyl-narwedine (XXI) 0.70 ml (0.68 mmol) =L-Selectride^((R)) 1 M in THF 1.2 equivalents 5 ml absolute THF

The educt was introduced into THF under N₂ atmosphere and cooled to −25°C., then L-Selectride was slowly added in drops. It was stirred for 30minutes at −15° C., whereby the initial suspension was in a clearsolution. Then, the reaction mixture was brought to room temperatureover 1 hour, hydrolyzed with 5 drops of water, stirred for 30 minutes,0.5 ml of concentrated aqueous NH₄OH was added, stirred for another 10minutes, 2 ml of concentrated NH₄OH was added again and finally it wasextracted with methylene chloride. The combined organic phases werewashed with saturated common salt solution, dried on sodium sulfate,filtered, and the solvent was drawn off, whereby 350 mg of crude productwas produced. This crude product was purified on a silica gel column(CHCl₃:MeOH=9:1), whereby a yellow oil was produced, which solidified byadding ether.

Yield: 120 mg (0.398 mmol=70% of theory) of a colorless powder

C₁₈H₂₃NO₃ [301.39]

TLC: R_(f)=0.43 (CHCl₃:MeOH=95:5), not to be separated from educt

¹H-NMR (200 MHz, CDCl₃): δ 6.54 (s, 1H), 6.10 (dd, J=10.2, 1.2 Hz, 1H),5.98 (dd, J=10.2, 4.7 Hz, 1H), 4.56 (bs, 1H), 4.12 (bs, 1H), 3.99 (d,J=15.6 Hz, 1H), 3.82 (s, 3H), 3.81 (d, J=15.6 Hz, 1H), 3.20 (ddd,J=14.2, 12.1, 2.1 Hz, 1H), 2.96 (dt, J=14.2, 3.4 Hz, 1H), 2.65 (ddd,J=15.7, 3.2, 1.5 Hz, 1H), 2.41 (s, 3H), 2.24 (s, 3H), 1.99 (ddd, J=15.5,5.0, 2.5 Hz, 2H), 1.60 (ddd, J=13.7, 4.0, 2.4 Hz, 1H);

¹³C-NMR (50 MHz, CDCl₃) δ 144.0 (s), 143.0 (s), 133.4 (s), 128.9 (s),127.4 (d+d), 127.0 (s), 126.6 (s), 113.6 (d), 88.3 (d), 61.9 (d), 55.7(q), 55.4 (t), 53.8 (t), 48.2 (s), 42.7 (q), 33.8 (t), 29.8 (t), 19.4(q)

Production of Hyodrobromide:

The reaction solution is hydrolyzed with ethanol (about half thereaction volume), stirred for 30 minutes, then brought to pH≦1 withconcentrated HBr and stirred overnight. The precipitate that is producedis suctioned off, washed with ethanol and dried.

Melting point: 246-250° C. (hydrobromide)

C₁₈H₂₄NO₃Br×0.5H₂O [391.30] % C % H % N Cld.: 55.25 6.44 3.58 Fnd.:55.21 6.39 3.56

EXAMPLE 89[(±)-(4aα,6α,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methylepigalanthamine (MH-31)

2.00 g (6.68 mmol) 1-methylnarwedine (XXI) 150 ml methanol 2.50 g (6.68mmol) cerium trichloride heptahydrate 0.50 g (13.4 mmol) = NaBH₄ 2equivalents

The educt was dissolved in methanol with heating and then cooled to 0°C., CeCl₃×7H₂O was added and stirred at 0° C. for about 30-60 minutes.Then, NaBH₄ was added in portions, it was stirred for another 2 hours at0-5° C., whereby a precipitate formed. The reaction mixture washydrolyzed with 5 ml of 2N HCl, methanol was distilled off in a vacuum,the residue was taken up with another 150 ml of 2N HCl, made basic withconcentrated NH₄OH (violet precipitate), extracted with ethyl acetate,the collected organic phases were washed with saturated common saltsolution, dried on sodium sulfate, filtered, and the solvent was drawnoff. As a crude product, an isomer mixture of 1-methylepigalanthamineand 1-methylgalanthamine at a ratio of about 5:1 was produced, whichcould be separated by chromatography (silica gel, CHCl₃:MeOH=9:1+0.5%NH₄OH).

Yield: 1.34 g (4.45 mmol=66.6% of theory) of a colorless oil

C₁₈H₂₃NO₃ [301.39]

TLC: R_(f)=0.20 (CHCl₃:MeOH=9:1)

¹H-NMR (200 MHz, CDCl₃): δ 6.51 (s, 1H), 6.10 (d, J=10.2 Hz, 1H), 5.79(d, J=10.2 Hz, 1H), 4.69-4.56 (m, 1H), 4.55 (bs, 1H), 3.96 (d, J=15.3Hz, 1H), 3.82 (s, 3H), 3.79 (d, J=15.3 Hz, 1H), 3.21 (td, J=13.1, 1.7Hz, 1H), 2.97 (dt, J=14.1, 3.3 Hz, 1H), 2.75 (dddd, J=14.1, 5.3, 4.0,1.2 Hz, 1H), 2.38 (s, 3H), 2.23 (s, 3H), 2.10 (dd, J=13.1, 3.2 Hz, 1H),2.03 (bs, 1H), 1.69 (ddd, J=13.6, 10.7, 2.6 Hz, 2H); ¹³C-NMR (50 MHz,CDCl₃) δ 145.0 (s), 142.9 (s), 133.5 (s), 131.7 (d), 128.5 (s), 126.7(d), 126.6 (s), 113.5 (d), 88.3 (d), 63.1 (d), 55.8 (q), 55.2 (t), 54.1(t), 48.3 (s), 42.6 (q), 34.6 (t), 32.4 (t), 19.5 (q)

Production of Hydrobromide:

The 1-methylepigalanthamine that was obtained was taken up in ethanoland brought to pH≦1 with concentrated HBr. The hydrobromide was broughtto crystallization under cold conditions and the precipitate that wasproduced was suctioned off, washed with cold ethanol and dried.

Melting point: 254-255° C. (hydrobromide)

C₁₈H₂₄NO₃Br×0.5 H₂O [391.30] % C % H % N Cld.: 56.25 6.44 3.58 Fnd.:56.28 6.21 3.57

EXAMPLE 90

[(±)-(4aα,6α,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methyl-N-demethylepigalanthamine

Method A (Epimerization of 1-methyl-N-demethylgalanthamine (XXII))

Step 1 (Acetylation):[(±)-(4aα,6α,8aR*)]-6-O-Acetyloxy-4a,5,9,10,11,12-hexahydro-3-methoxy-1-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine(MH-67)

100 mg (0.35 mmol) 1-methyl-N-demethylgalanthamine (XXII) 0.50 ml (1.74mmol) = N,N-dimethylformamide-bis(2,2- 5 equivalentsdimethylpropyl)-acetal 0.10 ml (1.74 mmol) = glacial acetic acid 5equivalents 12 ml toluene

The educt was heated in 10 ml of toluene under N₂ atmosphere to 80° C.and over 1 hour, a mixture that consists ofN,N-dimethylformamide-bis-(2,2-dimethylpropyl)acetal and glacial aceticacid in 2 ml of toluene was added in drops. After 22 hours at 80° C.,the cooled toluene phase was extracted 1× with water, then with 2Nhydrochloric acid, the acidic aqueous phase was made basic withconcentrated ammonia solution, it was extracted with ethyl acetate, theorganic phases were washed with saturated common salt solution, dried onsodium sulfate, filtered, and the solvent was drawn off. The residue waspurified by column chromatography.

(CHCl₃:MeOH=95:5).

Yield: 45 mg (0.14 mmol=39% of theory) of a colorless oil

C₁₉H₂₃NO₄ [329.40]

TLC: R_(f)=0.20 (CHCl₃:MeOH=95:5)

¹H-NMR (200 MHz, CDCl₃): δ 6.50 (s, 1H), 6.14 (d, J=10.2 Hz, 1H), 5.72(d, J=10.2 Hz, 1H), 5.67-5.58 (m, 1H), 4.57 (bs, 1H), 4.24 (d, J=16.0Hz, 1H), 3.83 (s, 3H), 3.75 (d, J=16.0 Hz, 1H), 3.40-3.09 (m, 2H),2.90-2.70 (m, 1H), 2.23 (s, 3H), 2.07 (s, 3H), 2.01-1.73 (m, 3H);¹³C-NMR (50 MHz, CDCl₃): δ 170.2 (s), 145.3 (s), 142.8 (s), 133.0 (s),130.5 (s), 128.4 (d), 127.2 (d) 127.0 (s), 113.5 (d), 87.3 (d), 66.4(d), 55.8 (q), 48.8 (s+t) 47.1 (t), 40.4 (t), 28.2 (t), 21.1 (q), 19.4(q)

Step 2: Ester Hydrolysis (MH-78)

 17 mg (0.05 mmol) 6-O-acetyl-1-methyl-N- demethylepigalanthamine(XXIIa) 0.5 ml methanol 0.1 ml 2N KOH  17 mg (0.12 mmol) = 2.4equivalents potassium carbonate

The reagents were stirred together at room temperature. After the end ofthe reaction, it was mixed with 1 ml of water, methanol was drawn off,it was acidified with 4 ml of 2N hydrochloric acid, the aqueous phasewas washed with ethyl acetate, then made basic with concentrated aqueousammonia solution and extracted with ethyl acetate. The organic phaseswere washed with saturated common salt solution, dried on sodiumsulfate, filtered, and the solvent was drawn off.

C₁₇H₂₁NO₃ [287.36]

TLC: R_(f)=0.07 (CHCl₃:MeOH=9:1)

Method B (Demethylation of 1-Methylepigalanthamine) (MH-94)

0.80 g (2.65 mmol) 1-methylepigalanthamine (XXIII) 1.50 g (6.63 mmol) =2.5 equivalents azodicarboxylic acid-bis-(2-methyl- 2-propylester) 80 mltetrahydrofuran

The reagents were stirred together at room temperature for 24 hours,then the solvent was drawn off. The residue was taken up intrifluoroacetic acid in methylene chloride, stirred for 30 minutes, madebasic in an ice bath with concentrated aqueous ammonia solution andextracted with methylene chloride. The organic phases were washed withsaturated common salt solution, dried on sodium sulfate, filtered, andthe solvent was removed. The crude product was purified by columnchromatography (CHCl₃:MeOH 9:1).

Yield: 400 mg (1.39 mmol=53% of theory) of a colorless oil

C₁₇H₂₁NO₃ [287.36]

TLC: R_(f)=0.10 (CHCl₃:MeOH=9:1)

¹H-NMR (200 MHz, CDCl₃): δ 6.50 (s, 1H), 6.08 (d, J=10.3 Hz, 1H), 5.80(d, J=10.3 Hz, 1H), 4.70-4.62 (m, 1H), 4.57 (bs, 1H), 4.26 (d, J=15.7Hz, 1H), 3.83 (s, 3H), 3.75 (d, J=15.7 Hz, 1H), 3.35-3.20 (m, 1H),2.85-2.70 (m, 1H), 2.50-2.29 (m, 2H), 2.23 (s, 3H), 2.00-1.64 (m, 2H);¹³C-NMR (50 MHz, CDCl₃): δ 145.4 (s), 142.9 (s), 133.5 (s), 131.6 (d),130.7 (s), 127.2 (d), 126.8 (s), 113.3 (d), 88.2 (d), 63.1 (d), 55.9(q), 48.9 (t), 48.8 (s), 47.2 (t), 32.2 (t), 28.2 (t), 19.5 (q)General Operating Instructions for Quaternary 1-Methyl- and1-Methylepi-galanthamine Derivatives (Examples 90-99)

The educt was dissolved* in very little DMF, added to the alkyl halide,and the reaction mixture was heated (generally not above the boilingtemperature of the alkyl halide, but at most 70° C.). By means of TLC,the end of the reaction was determined, then the reaction mixture wasslowly added in drops to ether while being stirred (in many cases easilyextrudes oil), the precipitate was suctioned off and washed with ether.For purification and for removing residual DMF, the precipitate wasdissolved in ethanol and once more precipitated in ethyl acetate, thendried in a vacuum drying oven at 50° C.

TLC: CHCl₃:MeOH=9:1, R_(f) generally slightly over the starting value.*With R═CH₂Cl, methylene chloride (p.A. 99.5%) is used as a solvent andreagent.

EXAMPLE 90[(±)-(4aα,6β,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium,chloride (MH-33)

(XLI)

280 mg (0.94 mmol) 1-methylgalanthamine (XV) 0.30 ml (3.08 mmol) =1-chloro-2-methylprop-2-ene 3 equivalents 5.00 ml dimethylformamide

The reaction was performed at 70° C. and worked up after 2 hours, by thereaction mixture having been added in drops to 25 ml of diethyl ether.

Yield: 270 mg (0.69 mmol=73% of theory) of a colorless powder

C₂₂H₃₀CINO₃ [391.94]

TLC: R_(f)=0.10 (CHCl₃:MeOH=9:1)

Melting point: 239-241° C.

C₂₂H₃₀ClNO₃×1.4H₂O [417.14] % C % H % N Cld.: 63.34 7.92 3.36 Fnd.:63.22 7.85 3.59

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.6 (s), 134.2 (s), 133.5 (s), 131.1 (s),130.9 (d), 127.5 (t), 124.9 (d), 115.9 (s), 114.4 (d), 86.3 (d), 73.0(t), 60.8 (t), 59.4 (d), 55.5 (q), 46.3 (s), 43.0 (q), 31.1 (t), 23.8(q), 18.9 (q)

EXAMPLE 91[(±)-(4aα,6β,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-(2-propinyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide (MH-38)

(XXIX)

349 mg (1.16 mmol) 1-methylgalanthamine (XV) 0.13 ml (1.16 mmol)3-bromo-1-propine (propargyl bromide) 4.00 ml dimethylformamide

The reaction was performed at 60° C. and worked up after 19 hours by thereaction mixture having been added in drops to 80 ml of diethyl ether.

Yield: 300 mg (0.71 mmol=62% of theory) of a beige powder

C₂₁H₂₆BrNO₃[420.35]

TLC: R_(f)=0.09 (CHCl₃:MeOH=9:1)

Melting point: 216-218° C.

C₂₁H₂₆BrNO₃×0.35H₂O×0.25 C₃H₇NO [444.93] % C % H % N Cld.: 58.72 6.443.90 Fnd.: 58.70 6.37 3.94

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.8 (s), 144.7 (s), 133.4 (s), 131.0 (s),125.2 (d), 115.3 (s), 114.5 (d), 86.2 (d), 83.7 (d), 72.6 (t), 60.6 (t),59.7 (d), 55.6 (q), 46.2 (s), 43.0 (g), 31.0 (t), 18.8 (q)

EXAMPLE 92[(±)-(4aα,6,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-phenylmethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide (MH-39)

(XL)

 242 mg (0.80 mmol) 1-methylgalanthamine (XV) 0.25 ml (1.01 mmol) = 1.4equivalents benzyl bromide 4.00 ml dimethylformamide

The reaction was performed at 60° C. and worked up after 10 minutes.

Yield: 262 mg (0.55 mmol=69% of theory) of a beige powder

C₂₅H₃₀BrNO₃ [472.42]

TLC: R_(f)=0.08 (CHCl₃:MeOH 9:1)

Melting point: 246-248° C. % C % H % N Cld.: 63.56 6.40 2.96 Fnd.: 63.356.34 2.93

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.7 (s), 133.4 (d), 130.7 (s), 130.4 (d),129.0 (d), 128.1 (s), 114.5 (d), 86.3 (d), 59.7 (t), 59.5 (d), 55.6 (q),46.2 (s), 18.6 (q)

EXAMPLE 93[(±)-(4aα,6β,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11,11-trimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium,iodide (MH-83)

(XLII)

140 mg (0.46 mmol) 1-methylgalanthamine (XV) 198 mg (1.39 mmol) = 3equivalents methyl iodide 4.00 ml dimethylformamide

The reaction was performed at 40° C. and worked up after 1.5 hours, bythe reaction mixtue having been added in drops to 30 ml of diethylether.

Yield: 146 mg (0.54 mmol=71% of theory) of a light brown powder

C₁₉H₂₆INO₃ [443.32]

TLC: R_(f)=0.05 (CHCl₃:MeOH=9:1)

Melting point: 278-280° C.

C₁₉H₂₆INO₃×0.3H₂O [448.72] % C % H % N Cld.: 50.86 5.97 3.12 Fnd.: 50.575.85 3.43

¹³C-NMR (50 MHz, DMSO-d₆) δ 144.6 (s), 144.1 (s), 132.8 (s), 131.6 (s),114.2 (d), 86.3 (d), 62.6 (t), 59.5 (d), 55.4 (q), 45.9 (s), 31.0 (t),18.4 (q)

EXAMPLE 94[(±)-(4aα,6β,8aR*))-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-(2-methyl-2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium,chloride (MH-66)

(XLIV)

150 mg (0.50 mmol) 1-methylepigalanthamine (XXIII) 45.0 mg (1.50 mmol) =1-chloro-2-methylprop-2-ene 3 equivalents 4.00 ml dimethylformamide

The reaction was performed at 70° C. and worked up after 100 minutes, bythe reaction mixture having been added in drops to 50 ml of diethylether.

Yield: 160 mg (0.41 mmol=82% of theory) of a colorless powder

C₂₂H₃₀ClNO₃ [391.94]

TLC: R_(f)=0.09 (CHCl₃:MeOH=9:1)

Melting point: 162-164° C.

C₂₂H₃₀CINO₃×0.7H₂O×0.15 C₃H₇O [415.51] % C % H % N Cld.: 64.90 7.87 3.88Fnd.: 64.77 7.68 3.95

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.7 (s), 134.2 (s), 134.1 (s) 131.1 (d),127.5 (t), 114.4 (d), 87.3 (d), 73.0 (t), 60.7 (d), 59.4 (t), 55.6 (q),46.3 (s), 23.8 (q), 18.9 (q)

EXAMPLE 95

[(±)-(4aα,6aα,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-(2-propinyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide (MH-71) (XLVIII)

150 mg (0.50 mmol) 1-methylepigalanthamine (XXIII) 180 mg (1.50 mmol) =3-bromo-1-propine (propargyl 3 equivalents bromide) 4.00 mldimethylformamide

The reaction was performed at 70° C. and worked up after 2.5 hours, bythe reaction mixture having been added in drops to 30 ml of diethylether.

Yield: 167 mg (0.40 mmol=82% of theory) of a light brown powder

C₂₁H₂₆BrNO₃ [420.35]

TLC: R_(f)=0.09 (CHCl₃:MeOH=9:1)

Melting point: 158-162° C.

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.8 (s), 133.9 (s), 131.2 (s), 114.5 (d),87.2 (d), 83.7 (d), 72.6 (d), 55.6 (q), 46.3 (s), 31.9 (t), 18.8 (q)

EXAMPLE 96[(±)-(4aα,6α,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-(2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide (MH-72)

(XLIX)

150 mg (0.50 mmol) 1-methylepigalanthamine (XXIII) 0.13 ml (1.50 mmol) =3-bromo-1-propene (allyl bromide) 3 equivalents 4.00 mldimethylformamide

The reaction was performed at 60° C. and worked up after 2 hours.

Yield: 150 mg (0.36 mmol=64% of theory) of a light brown powder

C₂₁H₂₈BrNO₃ [422.36]

TLC: R_(f)=0.11 (CHCl₃:MeOH=9:1)

Melting point: 140-145° C.

C₂₁H₂₈BrNO₃×1H₂O×0.25 C₃H₇NO [458.64] % C % H % N Cld.: 56.96 6.98 3.82Fnd.: 56.69 6.65 4.05

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.7 (s), 134.5 (d), 134.0 (s), 131.1 (s),128.3 (s), 126.1 (d), 115.3 (d), 114.4 (d), 87.2 (d), 60.7 (d), 59.8(t), 55.6 (q), 46.3 (s), 31.5 (t), 18.8 (q)

EXAMPLE 97[(±)-(4aα,6α,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-(4-(trifluoromethyl)phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide (MH-75)

(XLVI)

150 mg (0.50 mmol) 1-methylepigalanthamide (XXIII) 357 mg (1.50 mmol) =4-trifluoromethylbezyl bromide 1.4 equivalents 4.00 ml dimethylformamide

The reaction was performed at 70° C. and worked up after 1 hour.

Yield: 142 mg (0.26 mmol=53% of theory) of a light yellow powder

C₂₆H₂₉BrF₃NO₃ [540.42]

TLC: R_(f)=0.10 (CHCl₃:MeOH=9:1)

Melting point: 178-182° C.

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.8 (s), 134.4 (d+d), 134.2 (d), 132.6(s), 131.2 (s), 130.9 (s), 130.3 (s), 126.6 (d), 125.8 (s), 121.2 (d),114.5 (d), 87.3 (d), 60.8 (d), 55.6 (q), 46.3 (s), 34.3 (t), 18.7 (q)

EXAMPLE 98[(±)-(4aα,6α,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-11-(phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide (MH-76)

(XLV)

153 mg (0.51 mmol) 1-methylepigalanthamine (XXIII) 92 mg (0.51 mmol)benzyl bromide 4.00 ml dimethylformamide

The reaction was performed at 70° C. and worked up after 3 hours.

Yield: 150 mg (0.32 mmol 63% of theory) of a light brown powder

C₂₅H₃₀BrNO₃ [472.421

TLC: R_(f)=0.11 (CHCl₃:MeOH=9:1)

Melting point: 169-175° C.

¹³C-NMR (50 MHz, DMSO-d₆) δ 144.6 (s), 134.1 (s), 133.4 (d), 131.0 (s),130.4 (d), 128.9 (d), 128.1 (S), 114.4 (d), 87.2 (d), 61.8 (d), 59.4(t), 55.6 (q), 46.3 (s), 31.5 (t), 18.6 (q)

EXAMPLE 99[(±)-(4aα,6α,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11,11-trimethyl-6H-benzofuro[3a,3,2-ef)[2]benzazepinium,iodide (MH-81)

(XLVII)

210 mg (0.70 mmol) 1-methylepigalanthamine (XXIII) 290 mg (2.10 mmol) =methyl iodide 3 equivalents 4.00 ml dimethylformamide

The reaction was performed at 70° C. and worked up after 2 hours, by thereaction mixture having been added in drops to 30 ml of diethyl ether.

Yield: 240 mg (0.54 mmol=77% of theory) of a light-brown powder

C₁₉H₂₆INO₃ [443.32]

TLC: R_(f)=0.05 (CHCl₃:MeOH=9:1)

Melting point: decomposition>280° C. % C % H % N Cld.: 51.48 5.91 3.16Fnd.: 51.25 5.75 3.32

¹³C-NMR (50 MHz, DMSO-d₆): δ 144.7 (s), 133.6 (s), 131.1 (s), 114.4 (d),87.1 (d), 62.2 (t), 60.7 (q), 55.5 (q), 48.4 (d), 46.2 (s), 31.5 (t),18.9 (q)

General Operating Instructions for the Production ofGalanthamine-N-Oxides

EXAMPLES 100-101

1 equivalent galanthamine derivative 1-1.5 equivalents3-chloroperbenzoic acid 100 ml chloroform/1 g of galanthamine derivative0.7 ml H₂O₂ (35%)/1 g of galanthamine derivative

The 3-chloroperbenzoic acid is dissolved in ⅓ chloroform, mixed withhydrogen peroxide and stirred for 2 minutes. Then, this solution isadded to a solution of the galanthamine derivative in ⅔ chloroform, itis stirred for 15 minutes, concentrated by evaporation and purified bymeans of column chromatography (gradient: CHCl₃:MeOH=9:1→MeOH).

EXAMPLE 101[4aS-(4αa,6α,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,11-oxide, epigalanthamine-N-oxide (Pi-23)

49.7 mg (0.17 mmol) epigalanthamine (26) 29.9 mg (0.17 mmol)3-chloroperbenzoic acid 0.03 ml hydrogen peroxide (35%)   5 mlchloroform

Yield: 37 mg (71% of theory)

C₁₇H₂₁NO₄ [303.36]

TLC: R_(f)=0.05 (CHCl₃:MeOH 9:1)

¹H-NMR (200 MHz, CDCl₃) δ 6.67 (s, 2H), 5.96 (bs, 2H), 4.78 (d, J=15.0Hz, 1H), 4.67-4.50 (m, 2H), 4.26 (d, J=15.0 Hz, 1H), 3.83 (s, 3H),3.67-3.41 (m, 2H), 3.41 (s, 2H), 2.96 (s, 3H) 2.77 (dt, J=13.1, 3.7 Hz,1H), 2.05 (bs, 1H), 1.74 (t, J=11.3 Hz, 1H)

¹³C-spectra could not be taken up because of the quick solvate formationand crystallization in chloroform, but the structural determination wasmade by x-ray crystallography.

General Operating Instructions for the Production of N-Substituted1-Methylgalanthamine Derivatives

EXAMPLES 102-106

200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (or -epigalanthamine)192 mg (1.39 mmol) = potassium carbonate 2 equivalents 117 mg (0.78mmol) = sodium iodide 1.1 equivalents (0.84 mmol) = 1.2 substitutedalkyl halide equivalents 10 ml acetone, dried on a 4 Å molecular sieve

Sodium iodide, potassium carbonate and educt were thoroughly pulverizedin a friction column, the mixture together with some glass pellets wereintroduced into the flask and suspended in absolute acetone. Thesubstituted alkyl halide was added in measured quantities, and thereaction mixture was refluxed. After the end of the reaction, thereaction mixture was evaporated to the dry state in a vacuum, and theresidue was taken up with 2N HCl, the aqueous phase was washed withethyl acetate, then made basic with concentrated aqueous ammonia and inturn extracted with ethyl acetate. The collected organic phases werewashed with saturated common salt solution, dried on sodium sulfate,filtered, and the solvent was drawn off. The crude product was purifiedon a silica gel column (mobile solvent: CHCl₃:MeOH=9:1+1% NH₄OH)

EXAMPLE 102[(±)-(4aα,6β,8aR*)-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-(2-propenyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methyl-N-allylgalanthamine (MH-25)

(XXXIII)

200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 0.07 ml (0.84mmol) = 1-bromo-2-propene (allyl bromide) 1.2 equivalents

After 10 hours, the reaction was worked up.

Yield: 50 mg (0.15 mmol=22% of theory) of a yellow oil

C₂₀H₂₅NO₃ [327.43]

TLC: R_(f)=0.17 (CHCl₃:MeOH=9:1+1% NH₄OH)

C₂₀H₂₅NO₃×0.8H₂O [341.82] % C % H % N Cld.: 70.27 7.84 4.10 Fnd.: 70.187.60 4.05

¹H-NMR (200 MHz, CDCl₃): δ 6.52 (s, 1H), 6.12 (d, J=10.3 Hz, 1H),6.03-5.78 (m, 2H), 5.18 (bs, 1H), 5.11 (d, J=4.5 Hz, 1H), 4.57 (bs, 1H),4.12 (bs, 1H), 4.09 (d, J=15.0 Hz, 1H), 3.81 (s, 3H), 3.78 (d, J=15.0Hz, 1H), 3.32-3.02 (m, 4H), 2.72-2.58 (m, 1H), 2.21 (s, 3H), 2.07-1.89(m, 2H), 1.57 (ddd, J=13.7, 3.4, 2.7 Hz, 1H); ¹³C-NMR (50 MHz, CDCl₃): δ144.0 (s), 143.0 (s), 136.0 (d), 133.6 (s), 129.1 (s), 127.4 (d), 127.2(d) 126.9 (s), 117.5 (t), 113.7 (d), 88.4 (d), 62.0 (d), 57.2 (t), 55.8(q), 52.9 (t), 52.0 (t), 48.4 (s), 33.9 (t), 29.8 (t), 19.4 (q)

EXAMPLE 103[(±)-(4aα,6β,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-(phenylmethyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methyl-N-benzylgalanthamine (MH-26)

(XXXVI)

200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 0.1 ml (0.84mmol) = bromomethylbenzene (benzyl bromide) 1.2 equivalents

After 24 hours, the reaction was worked up.

Yield: 140 mg (0.37 mmol=53% of theory) of a yellow oil

C₂₄H₂₇NO₃ [377.481

TLC: R_(f)=0.36 (CHCl₃:MeOH=9:1+1% NH₄OH)

¹H-NMR (200 MHz, CDCl₃): δ 7.30 (m, 5H), 6.50 (s, 1H), 6.16 (d, J=10.2Hz, 1H), 5.99 (dd, J=10.2, 4.9 Hz, 1H), 4.61 (bs, 1H), 4.13 (bs, 1H),4.00 (d, J=15.7 Hz, 1H), 3.82 (s, 3H), 3.81 (d, J=15.7 Hz, 1H), 3.69 (s,2H), 3.34 (td, J=14.1, 12.4, 1.8 Hz, 1H), 3.13 (td, J=14.1, 3.5 Hz, 1H),2.74-2.37 (m, 2H) 2.19-1.93 (m, 2H), 1.90 (s, 3H), 1.57 (dt, J=13.7, 3.0Hz, 1H) ¹³C-NMR (50 MHz, CDCl₃): δ 143.9 (s), 143.0 (s), 138.9 (s),133.6 (s), 129.2 (s), 128.7 (d), 128.2 (d), 127.4 (d), 127.3 (d), 127.2(s), 126.9 (d), 113.7 (d), 88.4 (d), 62.0 (d), 57.4 (t), 55.8 (q), 52.4(t), 52.2 (t), 48.5 (s), 33.7 (t), 29.8 (t), 19.1 (q)

EXAMPLE 104[(±)-(4aα,6β,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-(2-(4-morpholinyl)ethyl)-6H-benzofuro[3a,3,2-ef][12]benzazepin-6-ol,1-methyl-N-morpholinoethyl-galanthamine (MH-28)

(XXXV)

200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 155 mg (0.84mmol) = 4-(2-chloroethyl)morpholine 1.2 equivalents hydrochloride

After 24 hours, the reaction was worked up.

Yield: 210 mg (0.52 mmol=75% of theory) of a yellow oil

C₂₃H₃₂N₂O₄ [400.52]

TLC: R_(f)=0.51 (CHCl₃:MeOH=9:1+1% NH₄OH)

C₂₃H₃₂N₂O₄×0.9H₂O [416.72] % C % H % N Cld.: 66.29 8.17 6.72 Fnd.: 66.288.09 6.85

¹H-NMR (200 MHz, CDCl₃): δ 6.52 (s, 1H), 6.10 (d, J=10.3 Hz, 1H), 5.97(dd, J=10.3, 4.8 Hz, 1H), 4.55 (bs, 1H), 4.13 (bs, 1H), 4.12 (d, J=15.9Hz, 1H), 2.88 (d, J=15.9 Hz, 1H), 3.81 (s, 3H), 3.75-3.65 (m, 4H), 3.30(ddd, J=14.3, 12.4, 2.0 Hz, 1H), 3.10 (dt, J=14.3, 3.3 Hz, 1H),2.76-2.58 (m, 4H), 2.55-2.41 (m, 5H), 2.25 (s, 3H), 2.08-1.90 (m, 2H),1.55 (dd, J=13.7, 2.8 Hz, 1H); ¹³C-NMR (50 MHz, CDCl₃): δ 144.1 (s),143.0 (s), 133.5 (s), 128.9 (s), 127.4 (d), 127.1 (d), 126.9 (s), 113.7(d), 88.4 (d), 66.7 (t+t), 66.6 (t), 61.9 (d), 57.1 (t), 55.8 (q), 54.0(t+t), 53.4 (t), 52.0 (t), 48.4 (s), 33.4 (t), 29.8 (t), 19.4 (q)

EXAMPLE 105[(±)-(4aα,6β,8aR*)-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-(3-(1-piperidinyl)propyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methyl-N-piperidinopropyl-galanthamine (MH-29)

(XXXIV)

200 mg (0.70 mmol) 1-methyl-N-demethylgalanthamine (XXII) 166 mg (0.84mmol) = 1-(3-chloropropyl)piperidine 1.2 equivalents hydrochloride

After 24 hours, the reaction was worked up.

Yield: 180 mg (0.44 mmol=63% of theory) of a yellow oil

C₂₅H₃₆N₂O₃ [412.581

TLC: R_(f)=0.27 (CHCl₃:MeOH=9:1+1% NH₄OH)

C₂₅H₃₆N₂O₃×0.50 H₂O [421.58] % C % H % N Cld.: 71.23 8.85 6.64 Fnd.:71.33 8.97 6.60

¹H-NMR (200 MHz, CDCl₃): δ 6.52 (s, 1H), 6.10 (d, J=10.4 Hz, 1H), 5.96(dd, J=10.4, 4.7 Hz, 1H), 4.55 (bs, 1H), 4.12 (bs, 1H), 4.08 (d, J=15.7Hz, 1H), 3.83 (d, J=15.7 Hz, 1H), 3.81 (s, 3H), 3.24 (ddd, J=14.2, 12.2,2.0 Hz, 1H), 3.07 (dt, J 14.2, 3.5 Hz, 1H), 2.71-2.13 (m, 10H), 2.24 (s,3H), 2.07-1.88 (m, 2H), 1.77-1.35 (m, 9H); ¹³C-NMR (50 MHz, CDCl₃): δ144.0 (s), 142.9 (s), 133.5 (s), 128.9 (s), 127.3 (d+d), 127.2 (s),113.7 (d), 88.4 (d), 62.0 (d), 57.2 (t), 55.8 (q), 54.5 (t+t+t), 53.3(t), 51.4 (t), 48.5 (s), 33.4 (t), 29.8 (t), 25.7 (t+t), 25.0 (t), 24.2(t), 19.5 (q)

EXAMPLE 106[(±)-(4aα,6α,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-1-methyl-11-(3-(1-piperidinyl)propyl)-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1-methyl-N-piperidinopropyl-epigalanthamine (MH-117)

(XXXVII)

100 mg (0.35 mmol) 1-methylepigalanthamine (XXIV) 83 mg (0.42 mmol) =(1-(3-chloropropyl)piperidine 1.2 equivalent hydrochloride

After 28 hours, the reaction was worked up.

Yield: 60 mg (0.15 mmol=42% of theory) of a light yellow oil

C₂₅H₃₆N₂O₃ [412.58]

TLC: R_(f)=0.12 (CHCl₃:MeOH=9:1)

¹H-NMR (200 MHz, CDCl₃): δ 6.50 (s, 1H), 6.10 (d, J=10.2 Hz, 1H), 5.78(dd, J=10.2, 1H), 4.70-4.57 (m, 1H), 4.54 (bs, 1H), 4.05 (d, J=15.2 Hz,1H), 3.82 (d, J=15.2 Hz, 1H), 3.82 (s, 3H), 3.25 (ddd, J=13.5, 12.8, 1.6Hz, 1H), 3.09 (dt, J=3.5, 2.5 Hz, 1H), 2.75 (dt, J=13.7, 4.1 Hz, 1H),2.56-2.27 (m, H), 2.23 (s, 3H), 2.08 (td, J=13.1, 4.0, 2H), 1.81-1.38(m, 9H); ¹³C-NMR (50 MHz, CDCl₃) δ 144.9 (s), 142.7 (s), 133.4 (s) 131.3(s), 128.3 (d+d), 127.0 (s), 113.2 (d), 88.1 (d), 63.0 (d), 57.2 (t),55.7 (q), 54.4 (t+t+t), 53.1 (t), 51.6 (t), 48.4 (s), 33.1 (t), 29.5(t), 25.6 (t+t), 24.8 (t), 24.1 (t), 19.5 (g)

General Operating Instructions for the Production of GalanthaminiumBromide Derivatives

EXAMPLES 107-109

1 equivalent a galanthaMine derivative 1 equivalent N-bromosuccinimide50 ml methylene chloride or chloroform, distilled via P₂O₅/1 g of agalanthamine derivative

The educt is dissolved in a solvent, and N-bromosuccinimide is addedwhile being stirred. A precipitate is immediately formed that issuctioned off after an appropriate length of time, washed and suctionedoff in the dry state.

The products that are thus obtained are generally very pure, but thelarge amount of solvent rather than a small amount is important sinceotherwise succinimide is pulled into the substances and the latter aresubsequently difficult to purify.

EXAMPLE 107[4aS-(4aα,6β,8aR*)-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide, galanthaminium bromide (MH-119)

200 mg (0.7 mmol) galanthamine (1) 124 mg (0.7 mmol) N-bromosuccinimide10 ml methylene chloride or chloroform, distilled via P₂O₅

The precipitate that was produced was suctioned off after 10 minutes.

Yield: 230 mg (0.63 mmol=90% of theory) of a light yellow powder

C₁₇H₂₀BrNO₃ [366.25]

TLC: R_(f)=0.58 (CHCl₃:MeOH=9:1+1% NH₄OH)

Melting point: 216-219° C.

C₁₇H₂₀BrNO₃×0.1 HBr [374.34] % C % H % N Cld.: 54.55 5.41 3.74 Fnd.:54.52 5.36 3.66

¹H-NMR (200 MHz, CDCl₃): δ 9.10 (s, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.27(d, J=8.5 Hz, 1H), 5.92 (dd, J=10.3, 4.5 Hz, 1H), 5.73 (d, J=10.3 Hz,1H), 4.74 (s, 1H), 4.59 (s, 1H), 4.11 (s, 2H), 3.94 (s, 3H), 3.79 (s,3H), 2.38 (d, J=15.3 Hz, 1H), 2.15 (m, 3H); ¹³C-NMR (50 MHz, CDCl₃): δ167.3 (d), 151.3 (s), 146.2 (s), 136.9 (s), 133.0 (d), 129.8 (d), 126.4(d), 115.0 (s), 112.9 (d), 87.0 (d), 58.9 (d), 56.4 (q), 54.0 (t), 51.5(q), 45.9 (s), 31.1 (t), 29.7 (t)

EXAMPLE 108[(±)-(4aα,6β,8aR*)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide, 1-methylgalanthaminium bromide (Pi-8)

200 mg (0.66 mmol) 1-methylgalanthamine (XV) 118 mg (0.66 mmol)N-bromosuccinimide 5 ml chloroform

After 5 minutes, an orange-yellow precipitate was produced, which wassuctioned off after 15 minutes. The precipitate 162 mg) was washed twicewith diethyl ether. The filtrate was concentrated by evaporation, takenup in a little ethanol and precipitated in diethyl ether (54 mg).

Yield: 216 mg (0.57 mmol=86% of theory) of an orange-yellow powder

C₁₈H₂₂BrNO₃ [380.28]

TLC: R_(f)=0.02 (CHCl₃:MeOH=9:1)

Melting point: 223-226° C.

C₁₈H₂₂BrNO₃×0.35 HBr [408.60] % C % H % N Cld.: 52.91 5.51 3.43 Fnd.:52.99 5.52 3.48

¹H-NMR (200 MHz, DMSO-d₆): δ 9.06 (s, 1H), 7.04 (s, 1H), 5.81 (dd,J=10.1, 4.5 Hz, 1H), 5.54 (d, J=10.2 Hz, 1H), 4.74 (s, 1H), 4.17-3.95(m, 4H), 3.91 (s, 3H), 3.86 (s, 3H), 2.53 (s, 3H), 2.40-1.96 (m, 4H);¹³C-NMR (50 MHz, DMSO-d₆): δ 166.4 (d), 150.5 (s), 144.7 (s), 140.4 (s),136.7 (s), 128.4 (d), 127.9 (d), 114.9 (d), 113.9 (s), 86.5 (d), 58.7(d), 56.3 (q), 54.4 (t), 50.5 (q), 47.0 (s), 35.1 (t), 29.4 (t), 18.9(q)

EXAMPLE 109[4aS-(4aa,6a,8aR*)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepinium,bromide, epigalanthaminium bromide (Pi-13)

0.78 g (2.71 mmol) epigalanthamine (26) 0.48 g (2.71 mmol)N-brornosuccinimide 6 ml absolute chloroform

After 3 minutes, a yellow precipitate was produced, which was suctionedoff and washed twice with diethyl ether. A second fraction was obtainedby concentration by evaporation of the filtrate and adding in drops ofdiethyl ether to a level of 60 ml. The second fraction was dissolved ina little ethanol for purification and added in drops to diethyl ether.

Yield: 0.91 g (2.48 mmol=92% of theory)

C₁₇H₂₀BrNO₃ [366.25]

TLC: R_(f)=0.05 (CHCl₃:MeOH=9:1+1% NH₄OH)

Melting point: 205-210° C.

C₁₇H₂₀BrNO₃ ×0.3 HBr [390.52] % C % H % N Cld.: 52.28 5.24 3.59 Fnd.:52.12 5.18 3.88

¹H-NMR (200 MHz, DMSO-d₆): δ 9.10 (s, 1H), 7.51 (d, J=11.5 Hz, 1H), 7.20(d, J=11.5 Hz, 1H), 5.82 (d, J=12.7 Hz, 1H), 5.68 (d, J=12.7 Hz, 1H),4.80 (bs, 1H), 4.40-4.21 (m, 1H), 4.21-4.04 (m, 2H), 3.94 (s, 3H), 3.77(s, 3H), 2.60 (s, 1H), 2.30-2.10 (m, 2H), 1.81-1.60 (m, 1H); ¹³C-NMR (50MHz, DMSO-d₆) 167.3 (d), 151.2 (s), 146.5 (s), 137.3 (s), 134.4 (d),133.0 (d), 126.0 (d), 115.0 (s), 113.0 (d), 88.0 (d), 60.7 (d), 56.4(q), 54.2 (t), 51.4 (q), 46.2 (s), 31.5 (t), 30.8 (t)

General Operating Instructions for the Production ofGalanthamine-12-Carbonitrile Derivatives

EXAMPLES 110-113

1 equivalent a galanthaminium derivative 3 equivalents potassium cyanide30 ml water/1 g of a galanthaminium derivative 10 ml diethyl ether/1 gof a galanthaminium derivative

The educt was dissolved in a separatory funnel in water, and thesolution was covered with a layer of ether, than solid potassium cyanide(freshly pulverized) was added thereto, whereby a white precipitateimmediately formed in the aqueous phase. After about 2-3 minutes, theproduct was extracted by shaking in the ether phase. The aqueous phasewas exhaustively extracted with ether and with sparingly solublederivatives with chloroform, the organic phases were combined, washedwith saturated aqueous common salt solution, dried on Na₂SO₄, filtered,and the solvent was drawn off. If necessary, the product that wasobtained was purified on a silica gel column (mobile solvent: CHCl₃:MeOH9:1, unless otherwise indicated).

EXAMPLE 110[4aS-(4aα,6β,8aR*)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile,galanthamine-12-carbonitrile (MH-123)

3.50 g (9.56 mmol) galantharninium bromide (L) 1.90 g (28.7 mmol) =potassium cyanide 3 equivalents  100 ml water 40.0 ml diethyl ether

The reaction was performed according to the general operatinginstructions.

Raw yield>2 g

The oily raw mixture, consisting of an isomer ratio of about 9:1, wasdissolved in as little ethanol as possible, and the main isomer wasbrought to crystallization while being stirred. The precipitate wassuctioned off, washed with ethanol, and the filtrate was combined withthe washing solution and concentrated by evaporation. The process wasrepeated until the main amount of pure main isomer was isolated.

Yield: 990 mg (3.28 mmol=34% of theory) of a white powder

C₈H₂₀N₂O₃ [312.37]

A mixture that consists of two isomers (ratio 9:1) and galanthamineremains, and said mixture is produced during the isolation of the mainisomer, which could be purified by columns. The isomer mixture is elutedagain at a ratio of 9:1 from the column, since it is converted into oneanother on the column.

TLC: R_(f)=0.77 main isomer

0.63 Secondary isomer (CHCl₃:MeOH=9:1)

Melting point: 151-155° C.

C₁₈H₂₀N₂O₃×0.1 H₂O [314.17] % C % H % N Cld.: 68.82 6.48 8.92 Fnd.:68.85 6.32 8.69

¹H-NMR (200 MHz, CDCl₃): δ 6.70 (s, 2H), 6.35 (d, J=10.2 Hz, 1H), 6.07(dd, J=10.2, 5.3 Hz, 1H), 4.71 (s, 1H), 4.61 (m, 1H), 4.15 (dt, J=11.1,5.0 Hz, 1H), 3.85 (s, 3H), 3.50 (dd, J=15.0, 13.6 Hz, 1H), 2.91 (dt,J=15.0, 3.2 Hz, 1H), 2.74-2.61 (m, 1H), 2.61 (s, 3H), 2.38 (d, J=11.4Hz, 1H), 1.98-2.08 (m, 2H), 1.78 (ddd, J=13.7, 5.0, 1.2 Hz, 1H); ¹³C-NMR(50 MHz, CDCl₃): δ 146.7 (s), 145.6 (s), 132.9 (s), 128.2 (d), 126.9(d), 124.2 (s), 122.5 (s), 111.6 (d), 88.9 (d), 61.6 (d+d), 55.9 (q),49.9 (t), 48.1 (s), 46.1 (q), 36.4 (t), 29.7 (t)

EXAMPLE 111[(±)-(4aα,6β,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile,1-methylgalanthamine-12-carbonitrile (Pi-12)

300 mg (0.79 mmol) 1-methylgalanthaminium bromide (LI) 154 mg (2.36mmol) = potassium cyanide 3 equivalents 20.0 ml water

205 mg of a white crude product was isolated.

An attempt was made to achieve column-chromatographic separation of thediastereomers with a pure ethyl acetate as a mobile solvent. In thiscase, however, no separation of the diastereomer mixture could beaccomplished.

Yield: 151 mg (0.46 mmol=59% of theory)

C₁₉H₂₂N₂O₃ [326.39]

TLC: R_(f)=0.20/0.65 (diastereomer mixture; ethyl acetate)

Melting point: 72-73° C.

C₁₉H₂₂N₂O₃×0.5 H₂O [335.39] % C % H % N Cld.: 68.04 6.91 8.35 Fnd.:67.91 6.62 8.20

¹H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDCl₃): δ 6.59 (s,1H), 6.31 (d, J=8.9 Hz, 0.4H), 6.27 (d, J=8.9 Hz, 0.6H), 6.01 (dd,J=9.2, 5.0 Hz, 1H), 4.96 (s, 0.6H), 4.83 (s, 0.4H), 4.57 (bs, 0.6H),4.50 (bs, 0.4H), 4.12 (dt, J=15.5, 4.9 Hz, 1H), 3.83 (s, 3H), 3.47 (ddd,J=13.9, 9.8, 3.4 Hz, 1H), 2.88 (dt, J=14.6, 3.8 Hz, 1H), 2.70 (bs, 1H),2.62 (s, 1.8H), 2.60 (s, 1.2H), 2.31 (s, 3H), 2.10-1.92 (m, 2H),1.87-1.68 (m, 1H); ¹³C-NMR (mixture that consists of 2 isomers, 100 MHz,CDCl₃): δ 145.5 (s), 145.4 (s), 145.3 (s), 144.8 (s), 135.7 (s), 133.6(s), 129.7 (d), 129.3 (d), 129.6 (s), 128.7 (s), 128.4 (d), 127.7 (d),122.9 (s), 122.8 (s), 116.7 (s), 115.3 (s), 114.5 (d), 114.4 (d), 89.4(d), 88.9 (d), 62.3 (d), 62.2 (d), 57.9 (d), 56.6 (d), 56.5 (q), 56.3(q), 51.0 (t), 50.3 (t), 49.0 (s), 47.9 (s), 47.2 (q), 47.2 (s), 36.8(t), 33.7 (t), 30.2 (t), 20.3 (q), 19.3 (q)

EXAMPLE 112[4aS-(4aa,6a,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile,epigalanthamine-12-carbonitrile (Pi-14)

500 mg (1.37 mmol) epigalanthaminium bromide (LII) 270 mg (4.10 mmol) =potassium cyanide 3 equivalents 15.0 ml water

Yield: 0.33 g (1.06 mmol=77% of theory)

C₁₈H₂₀N₂O₃ [312.37]

TLC: R_(f)=0.75 (CHCl₃:MeOH=9:1)

Melting point: 90-96° C.

¹H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDCl₃): δ 6.92 (d,J=8.3 Hz, 0.3H), 6.72 (d, J=8.0 Hz, 0.3H), 6.68 (d, J=8.0 Hz, 0.7H),6.62 (d, J=8.3 Hz, 0.7H), 6.31 (dt, J=10.5, 1.6 Hz, 0.7H); 6.03 (d,J=10.5 Hz, 0.3H), 5.85 (d, J=10.3 Hz, 1H), 5.22 (s, 0.3H), 4.64 (s,0.7H), 4.58 (bs, 1H), 3.86 (s, 0.9H), 3.85 (s, 2.1H), 3.12 (dt, J=14.8,3.2 Hz, 0.3H), 2.98-2.70 (m, 1.7H), 2.58 (s, 2.1H), 2.38 (s, 0.9H),2.27-2.04 (m, 1.2H), 1.85 (dd, J=13.5, 4.2 Hz, 1.4H), 1.71 (ddd, J=13.5,10.7, 2.5 Hz, 1.4H); ¹³C-NMR (mixture that consists of 2 isomers, 50MHz, CDCl₃): δ 147.5 and 147.2 (s), 145.2 and 145.0 (s), 132.6 (s),132.5 and 131.9 (d), 126.6 (d), 124.0 and 123.3 (s), 121.8 and 120.1(d), 116.5 (s), 111.3 and 111.2 (d), 88.7 and 88.4 (d), 62.8 (d), 61.4and 58.4 (d), 55.8 (q), 50.0 (t), 47.9 (s), 45.9 (q), 36.9 (t), 32.0 and31.7 (t)

EXAMPLE 113[(±)-(4aα,6α,8aR*)]-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-1,11-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-12-carbonitrile,1-methylepigalanthamine-12-carbonitrile (Pi-19)

1-Methylepigalanthaminium bromide was produced according to generaloperating instructions for the production of galanthaminium derivatives,whereby no precipitate formed, however. The reaction solution wastherefore evaporated to the dry state, the remaining residue was takenup in ether, suctioned off and washed. The remaining crude product wasused directly in the subsequent reaction according to NMR analysis. 500mg (1.32 mmcl) 1-methylepigalanthaminium bromide (LIII) 260 mg (3.96mmol) = 3 potassium cyanide equivalents 50 ml water

The purification was carried out by means of column chromatography(CHCl₃:MeOH=9:1).

Yield: 220 mg (0.67 mmol=51% of theory) of a white foam

C₁₉H₂₂N₂O₃ [326.391

TLC: R_(f)=0.70/0.60 (diastereomer mixture; CHCl₃:MeOH=9:1)

¹H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDCl₃): δ 6.57 (s,1H), 6.26 (d, J=10.4 Hz, 1H), 5.82 (d, J=10.4 Hz, 1H), 4.94 and 4.82 (s,1H), 4.74-4.55 (m, 1H), 4.50 and 4.45 (m, 1H), 3.87 and 3.84 (s, 3H),3.55-3.32 (m, 1H), 3.05-2.68 (m, 2H), 2.58 and 2.57 (s, 3H), 2.33 and2.30 (s, 3H), 2.23-2.07 (m, 1H), 1.93-1.63 (m, 2H); ¹³C-NMR (mixturethat consists of 2 isomers, 50 MHz, CDCl₃): δ 146.0 (s), 145.8 (s),144.5 (s), 144.1 (s), 135.0 (s), 133.0 (s), 132.2 (d), 131.7 (d), 129.5(d), 128.5 (s), 127.6 (s), 127.1 (d), 122.4 (s), 122.2 (s), 116.4 (s),114.8 (s), 113.9 (d), 113.8 (d), 88.5 (d), 88.4 (d), 63.0 (d), 62.6 (d)57.2 (d), 56.4 (d), 56.0 (q), 55.8 (q), 50.7 (t), 50.0 (t), 48.4 (s),47.3 (s), 46.7 (q), 36.9 (t), 34.1 (t), 31.7 (t), 19.8 (q) 18.8 (q)

General Operating Instructions for the Production of12-Methylqalanthamine Derivatives

EXAMPLES 114-117

1 equivalent a galanthaminium derivative 2-4 equivalents methylmagnesiumiodide (3 M in diethyl ether) 20 ml absolute diethyl ether/1 g of agalanthaminium derivative

The entire amount of Grignard reagent was introduced under N₂atmosphere, and then the solid galanthaminium derivative was addedwithout solvent. After the length of time indicated in each case,diethyl ether was added and stirred for a specific length of time,whereby the solid material dissolved. Then, it was hydrolyzed withwater, the reaction solution was made basic with concentrated ammoniaand extracted with ethyl acetate. The organic phases were washed withsaturated common salt solution, dried on sodium sulfate, filtered, andthe solvent was drawn off.

EXAMPLE 114[4aS-(4aa,6β,8aR)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11,12-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,12-methylgalanthamine (Pi-4)

2.00 g (5.46 mmol) galanthaminium bromide (L) 6.70 ml (20.2 mmol) =methylmagnesium iodide (3 M in 3.7 equivalents diethyl ether) 40 mlabsolute diethyl ether

After 40 minutes, the solvent was added and stirred for 5 hours, beforeit was hydrolyzed.

Yield: 760 mg (2.52 mmol=46% of theory) of a light yellow foam

C₁₈H₂₃NO₃ [301.38]

TLC: R_(f)=0.65 (CHCl₃:MeOH=9:1+1% NH₄OH)

Melting point: 46-48° C.

¹H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDCl₃): δ 6.66 (d,J=8.3 Hz, 0.8H), 6.65 (s, 0.2H), 6.64 (s, 0.2H), 6.57 (d, J=8.3 Hz,0.8H), 6.13 (d, J=10.1 Hz, 0.2H), 6.07 (d, J=10.1 Hz, 0.8H), 5.94 (dd,J=10.1, 4.4 Hz, 1H), 4.54 (bs, 1H), 4.26 (q, J=7.0 Hz, 0.2H), 4.08 (t,J=4.4 Hz, 1H), 3.88 (q, J=7.4 Hz, 0.8H), 3.80 (s, 0.6H), 3.78 (s, 2.4H),3.62 (ddd, J=14.6, 13.2, 1.0 Hz, 0.8H), 3.45 (d, 14.2 Hz, 0.2H), 3.12(dt, J=14.8, 3.3 Hz, 0.2H), 2.85 (td, J=15.5, 3.5 Hz, 0.8H), 2.76 (bs,1H), 2.63 (d, J=15.6 Hz, 1H), 2.43 (s, 3H), 2.16 (d, J=2.7 Hz, 0.2H),1.98 (dt, J=15.5, 2.3 Hz, 0.8H), 1.95 (dd, J=15.5, 2.3 Hz, 0.2H), 1.51(d, J=7.3 Hz, 2.4H), 1.47 (d, J=7.3 Hz, 0.6H); ¹³C-NMR (mixture thatconsists of 2 isomers, 50 MHz, CDCl₃): δ 146.1 and 145.6 (s), 143.8 and143.4 (s), 134.9 and 132.6 (s), 132.4 and 131.3 (s), 129.3 (d), 127.6and 127.3 (d), 126.9 (d), 122.0 and 119.9 (d), 111.5 and 110.8 (d), 88.6and 88.5 (d), 64.0 (d), 61.9 and 61.6 (d), 58.3 and 55.7 (q), 48.8 (s),44.1 (t), 41.3 (q), 31.5 and 31.0 (t), 29.9 and 29.7 (t), 21.8 and 17.5(q)

EXAMPLE 115[4aS-(4a?,6?,8aR*,12R*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11,12-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,(=12-methylgalanthamine); (main isomer)

The isomer mixture was purified by column chromatography on silica gel(CHCl₃:MeOH=9:1+1% NH₄OH), whereby a pure isomer was obtained.

¹H-NMR (200 MHz, CDCl₃): δ 6.66 (d, J=8.3 Hz, 1H), 6.57 (d, J=8.3 Hz,1H), 6.07 (d, J=10.1 Hz, 1H), 5.94 (dd, J=10.1, 4.4 Hz, 1H), 4.54 (bs,1H), 4.08 (t, J=4.4 Hz, 1H), 3.88 (q, J=7.4 Hz, 1H), 3.78 (s, 3H), 3.62(dd, J=14.6 (13.2 Hz, 1H), 2.85 (td, J=15.5, 3.5 Hz, 1H), 2.63 (d,J=15.6 Hz, 1H), 2.43 (s, 3H), 2.11 (dt, J=13.3, 2.4 Hz, 1H), 1.95 (ddd,J=16.5, 5.0, 1.8 Hz, 1H), 1.51 (d, J=7.3 Hz, 3H), 1.47 (dd, J=13.3 Hz,1H); ¹³C-NMR (50 MHz, CDCl₃) δ 146.2 (s), 143.5 (s), 135.1 (s), 131.4(s), 129.4 (d), 127.4 (d), 122.2 (d), 111.6 (d), 88.8 (d), 64.0 (d),61.8 (d), 55.8 (q), 48.9 (s), 44.2 (t), 41.5 (q), 31.7 (t), 29.8 (t),21.9 (q)

EXAMPLE 116[(±)-(4aα,6β,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-6H-1,11,12-trimethyl-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,1,12-dimethylgalanthamine (Pi-21)

500 mg (1.31 mmol) 1-methylgalanthaminium bromide (LI) 1.00 ml (3.00mmol) = methylmagnesium iodide (3 M in 2.3 equivalents diethyl ether) 15ml absolute diethyl ether

During the addition of educt, 5 ml of diethyl ether was added to keepthe reaction mixture stirrable. After the addition of educt wascompleted (30 minutes), another 10 ml of diethyl ether was added. After2.5 hours, the reaction mixture was hydrolyzed.

Yield: 73 mg (0.23 mmol 18% of theory) C₁₉H₂₅NO₃ [315.41]

TLC: R_(f)=0.50 (CHCl₃:MeOH=9:1+1% NH₄OH)

Melting point: 45-50° C.

¹H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDCl₃): δ 6.57 (s,1H), 6.06 (d, J=10.2 Hz, 1H), 5.95 (dd, J=10.2, 4.5 Hz, 1H), 4.59-4.44(m, 1H), 4.17-4.03 (m, 2H), 3.81 (s, 3H), 3.75-3.55 (m, 1H), 2.97-2.77(m, 1H), 2.73-2.55 (m, 1H), 2.51 (s, 0.5H), 2.46 (s, 2.5H), 2.25 (s,3H), 2.15-1.87 (m, 2H), 1.51 (d, J=7.3 Hz, 3H), 1.30-1.18 (m, 1H);¹³C-NMR (mixture that consists of 2 isomers, 50 MHz, CDCl₃) δ 144.7 (s),142.9 (s) 132.5 and 131.7 (s), 130.4 and 129.0 (s), 129.3 (d), 127.8 and126.8 (s), 127.5 (d), 114.3 and 114.0 (d), 88.7 and 88.4 (d), 62.2 and61.8 (d), 59.3 and 58.8 (d), 56.0 and 55.8 (q), 49.4 and 48.4 (s), 44.3(t), 41.5 (q), 31.7 (t), 29.9 (t), 19.7 and 19.2 (q), 18.8 (q)

EXAMPLE 117[(4aS-(4aa,6a,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11,12-dimethyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,12-methylepigalanthamine (Pi-22)

300 mg (0.82 mmol) epigalantharninium bromide (LII) 1.00 ml (3.00 mmol)= methylmagnesium iodide (3 M in 3.70 equivalents diethyl ether)

The Grignard reagent was added over 30 minutes, then 5 ml of ether wasadded. After 20 minutes, another 15 ml of ether was added and hydrolyzedfor 3 hours.

The purification was carried out by column chromatography(CHCl₃:MeOH=9:1)

Yield: 60 mg (0.20 mmol=24% of theory)

C₁₈H₂₃NO₃ [301.391

TLC: R_(f)=0.78 (CHCl₃:MeOH=9:1+1% NH₄OH)

¹H-NMR (200 MHz, CDCl₃): δ 6.65 (d, J=8.3 Hz, 1H), 6.53 (d, J=8.3 Hz,1H), 6.04 (d, J=10.4 Hz, 1H), 5.76 (d, J=10.4 Hz, 1H), 4.70-4.57 (m,1H), 4.54 (bs, 1H), 3.93-3.82 (m, 1H), 3.81 (s, 3H), 3.61 (t, J=13.6 Hz,1H), 2.94-2.67 (m, 3H), 2.41 (s, 3H), 2.20 (td, J=13.2, 2.4 Hz, 1H),1.69 (ddd, J=13.6, 10.6, 2.0 Hz, 1H), 1.52 (d, J=7.3 Hz, 3H), 1.59-1.44(m, 1H); ¹³C-NMR (50 MHz, CDCl₃): δ 147.0 (s), 143.2 (s), 134.5 (s),131.3 (d), 131.1 (s), 128.9 (d), 121.5 (d), 111.2 (d), 88.6 (d), 64.1(d), 62.7 (d), 55.6 (q), 48.6 (s), 44.4 (t), 41.2 (q), 32.0 (t+t), 21.8(q)

EXAMPLE 118[4aS-(4αa,6β,8aR*)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-12(11H)-one(MH-128)

200 g (0.64 mmol) galanthamine-12-carbonitrile (LV) 0.64 ml (0.64 mmol)sodium trimethylsilanolate (1 M in CH₂Cl₂) 5 ml absolute tetrahydrofuran

The educts were stirred under N₂ atmosphere at room temperature for 72hours, whereby a precipitate formed, which was suctioned off, washedwith tetrahydrofuran and dried.

Yield: 177 mg (0.59 mmol=92% of theory) of a light yellow powder

C₁₇H₁₉NO₄ [301.35]

TLC: R_(f)=0.65 (CHCl₃:MeOH=9:1)

Melting point: 251-255° C.

¹H-NMR (200 MHz, CDCl₃): δ 7.49 (d, J=8.5 Hz, 1H), 6.89 (d, J=8.5 Hz,1H), 5.87 (dd, J=9.8, 5.3 Hz, 1H), 5.53 (d, J=9.8 Hz, 1H), 4.74 (bs,1H), 4.13 (dt, J=10.1, 4.8 Hz, 1H), 3.91 (s, 3H), 3.80 (dt, J=14.1, 2.1Hz, 1H), 3.25-3.16 (m, 1H), 3.19 (s, 3H), 2.71 (dt, J=15.7, 1.7 Hz, 1H),2.31 (dt, J=14.1, 3.9 Hz, 1H), 2.06 (ddd, J=15.7, 5.0, 2.3 Hz, 1H), 1.83(dt, J=14.6, 2.5 Hz, 1H); ¹³C-NMR (50 MHz, CDCl₃) δ 168.3 (s), 146.9(s), 145.1 (s), 131.7 (s), 131.6 (d), 125.2 (d), 124.4 (d), 123.4 (s),111.9 (d), 89.2 (d), 61.0 (d), 55.8 (q), 49.5 (t), 48.0 (S), 38.3 (t),34.9 (q), 29.3 (t)

EXAMPLE 119[4aS-(4aα,6β,8aR*)]-4a,5,9,10-Tetrahydro-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,11-oxide (MH-142)

4.25 g (15.55 mmol) demethylgalanthamine (27) 35 mg (0.77 mmol) = 5%selenium dioxide 70 ml 10% aqueous H₂O₂ solution (35%) in acetone(oxidation solution)

Demethylgalanthamine was dissolved in the oxidation solution in anenvironment devoid of atmospheric humidity and cooled to 0°. Then, SeO₂was added, and it was stirred first for 20 minutes at 0° C. and then for4 hours at room temperature, whereby a white precipitate settled out,which was suctioned off, washed with acetone and dried. The filtrate wasmixed with water, the acetone was distilled off in a vacuum, and theremaining aqueous phase was extracted with methylene chloride. Thecollected organic phases were washed with saturated common saltsolution, dried on sodium sulfate, filtered, and the solvent was drawnoff. The oily residue was taken up in acetone, whereby a precipitatesettled out, which could be obtained as a second fraction. By repeatedconcentration by evaporation of the filtrate and taking-up in acetone,other fractions were obtained.

Yield: 3.53 g (12.29 mmol=79% of theory) of a white powder

C₁₆H₁₇NO₄ [287.31]

TLC: R_(f)=0.42 (CHCl₃:MeOH 9:1+1% concentrated NH₄OH)

Melting point: 232-233° C. (CHCl₃); release of a liquid starting from215° C.

C₁₆H₁₇NO₄×0.2 H₂O [290.91] % C % H % N Cld.: 66.06 6.03 4.81 Fnd.: 66.116.05 4.73

¹H-NMR (200 MHz, DMSO-d₆): δ 7.82 (s, 1H), 6.90 (s, 2H), 5.81 (dd,J=10.1, 4.4 Hz, 1H), 5.54 (d, J=10.1 Hz, 1H), 4.64 (bs, 1H), 4.36 (d,J=5.5 Hz, 1H), 4.14-4.02 (m, 2H), 3.79 (s, 3H), 2.39-1.99 (m, 4H);¹³C-NMR (50 MHz, DMSO-d₆): δ 146.1 (s), 144.6 (s), 134.6 (d), 131.8 (s),128.3 (d), 127.6 (d), 122.4 (d) 118.3 (s), 112.6 (d), 86.7 (d), 61.8(d), 59.1 (t), 55.7 (q) 45.3 (s), 34.2 (t), 29.7 (t)

EXAMPLE 119[4aS-(4aα,6β,8aR*)]-4a,5,9,10,13,14a-Hexahydro-6-hydroxy-3-methoxy-6H,14H-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-13(or 14)-carboxylic acid, methyl ester (MH-143)

175 mg (0.61 mmol) galanthamine nitrone (LXXXIV) 0.05 ml (0.61 mmol)acrylic acid methyl ester 6 ml absolute toluene

The reagents were refluxed for 48 hours under argon atmosphere, then thesolvent was drawn off. The residue was purified by column chromatography(CHCl₃:MeOH=9:1+1% concentrated NH₄OH).

Yield: 225 mg (0.60 mmol=99% of theory) of a light brown, glass-likesolidifying oil

C₂₀H₂₃NO₆ [373.40]

TLC: R_(f)=0.74 (CHCl₃:MeOH=9:1+1% concentrated NH₄OH)

C20H23NO6×0.5 H₂O [382.40] % C % H % N Cld.: 62.82 6.33 3.66 Fnd.: 62.886.17 3.65

Mixture that consists of stereoisomers and regioisomers. The morespecific treatment of spectra is found in Chapter 2.2,Strukturaufklärungen [Structural Explanations].

EXAMPLE 120(4aS-(4aα,6β,8aR*,14aS)]-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-6H,14aH-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-14-carboxylicacid, methyl ester (MH-145)

200 mg (0.70 mmol) galanthamine nitrone (LXXXIV) 0.06 ml (0.70 mmol)acetylenecarboxylic acid methyl ester (propiolic acid methyl ester) 5 mlabsolute toluene

The reagents were refluxed for 10 minutes under argon atmosphere,whereby the solution was already colored orange during heating, then thesolvent was drawn off. The residue was purified by column chromatography(CHCl₃:MeOH=9:1). The oily residue was recrystallized from ethanol,whereby yellow needles were obtained.

Yield: 261 mg (0.70 mmol=100% of theory) of light yellow needles

C₂₀H₂₁NO₆ [371.39]

TLC: R_(f)=0.73 (CHCl₃:MeOH=9:1)

Melting point: 151-154° C. % C % H % N Cld.: 64.68 5.70 3.77 Fnd.: 64.595.89 3.67

¹H-NMR (200 MHz, CDCl₃): δ 7.54 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.74(d, J=8.4 Hz, 1H), 5.96-5.77 (m, 2H), 5.67 (s, 1H), 4.55 (bs, 1H), 4.10(bs, 1H), 3.85 (s, 3H), 3.68 (s, 3H), 3.59 (ddd, J=14.3, 6.8, 3.8 Hz,1H), 3.30 (ddd, J=12.9, 9.3, 3.4 Hz, 1H), 2.64 (dd, J=15.7, 3.7 Hz, 1H),2.15 (td, J=7.7, 3.4 Hz, 1H), 2.01 (ddd, J=15.6, 5.3, 1.9 Hz, 1H), 1.54(ddd, J=15.6, 6.7, 3.5 Hz, 2H); ¹³C-NMR (50 MHz, CDCl₃): δ 163.9 (s),154.6 (d), 146.8 (s), 145.1 (s), 133.3 (s), 130.3 (d), 126.9 (d), 125.3(s), 123.3 (d), 111.3 (d), 109.9 (s), 89.1 (d), 68.7 (d), 61.4 (d), 55.8(q), 52.4 (t), 51.4 (q), 47.2 (s), 29.2 (t), 28.0 (t)

EXAMPLE 121[4aS-(4aα,6β,8aR*)-4a,5,9,10,13,14a-Hexahydro-6-hydroxy-3-methoxy-6H,14H-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-13(or 14)-carbonitrile (MH-146)

200 mg (0.70 mmol) galanthamine nitrone (LXXXIV) 0.05 ml (0.70 mmol)acrylonitrile 5 ml absolute toluene

The reagents were refluxed for 2 hours under argon atmosphere, then thesolvent was drawn off. The residue was purified by column chromatography(CHCl₃:MeOH=9:1).

Yield: 230 mg (0.68 mmol=97% of theory) of a light yellow oil

C₁₉H₂₀N₂O₄ [340.38]

TLC: R_(f)=0.74 (CHCl₃:MeOH=9:1)

C₁₉H₂₀N₂O₄×0.2H₂O [343.98] % C % H % N Cld.: 66.34 5.98 8.14 Fnd.: 66.226.03 7.86

Mixture that consists of 4 stereoisomers and regioisomers. The morespecific treatment of spectra is found in Chapter 2.2,Strukturaufklärungen.

EXAMPLE 122[(4aS-(4aα,6β,8aR*,14aS*)]-4a,5,9,10,13,14a-Hexahydro-6-hydroxy-3-methoxy-6H,14aH-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-6,13-diol,13-acetate (MH-153)

200 mg (0.70 mmol) galanthamine nitrone (LXXXIV) 0.24 ml (2.10 mmol) =vinyl acetate 4 equivalents 5 ml absolute toluene

The reagents were refluxed for 4 days under N₂ atmosphere, whereby eachday, 1 equivalent of vinyl acetate was added. The solvent was then drawnoff, and the residue was purified by column chromatography(CHCl₃:MeOH=9:1). The purified oil was crystallized from methanol.

Yield: 256 mg (0.69 mmol=98% of theory) of beige crystals

C₂₀H₂₃NO₆ [373.41]

TLC: R_(f)=0.70 (CHCl₃:MeOH=9:1)

Melting point: 132-134° C.

C₂₀H₂₃NO₆×0.6 H₂O [384.21] % C % H % N Cld.: 62.52 6.35 3.65 Fnd.: 62.596.12 3.61

¹H-NMR (Mixture that consists of 2 isomers, 200 MHz, CDCl₃): δ 6.76 and6.73 (d, J=8.3 Hz, 1H), 6.68 and 6.60 (d, J=7.7 Hz, 1H), 6.36 (d, J=4.1Hz, 1H), 6.30 (d, J=10.6 Hz, 1H), 6.08-5.91 (m, 1H), 4.60 and 4.50 (bs,1H), 4.32 (dd, J=11.3, 5.6 Hz, 1H), 4.13 (bs, 1H), 3.84 (s, 3H), 3.80(dd, J=19.1, 9.8 Hz, 1H), 3.22 (ddd, J=10.0, 6.8, 2.8 Hz, 1H), 2.92 (dd,J=12.3, 5.8 Hz, 1H), 2.78-2.57 (m, 2H), 2.09 (s, 3H), 2.07-1.79 (m, 2H);¹³C-NMR (Mixture that consists of 2 isomers, 50 MHz, CDCl₃): δ 169.6(s), 145.8 (s), 143.8 (s), 134.1 (s), 129.8 (d), 128.0 and 127.7 (d),127.0 (s), 118.7 and 118.5 (d), 111.4 and 110.9 (d), 95.3 and 94.5 (d),88.7 and 88.2 (d), 61.4 (d+d), 55.7 and 55.5 (q), 54.5 (t), 47.3 (s),41.7 (t), 29.7 (t), 29.3 (t), 21.0 and 20.9 (q)

EXAMPLE 123[4aS-(4aα,6β,8aR*,14aS*)-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-6H,14aH-benzofuro[3a,3,2-ef]isoxazolo[3,2-a][2]benzazepine-14-carbonitrile(MH-159)

500 mg (1.74 mmol) galanthamine nitrone (LXXXIV) 90 mg (1.74 mmol)acetylene carbonitrile 10 ml absolute toluene

The reagents were stirred for 7 days under argon atmosphere at roomtemperature, whereby the solution was colored yellow, then the solventwas drawn off. The residue was crystallized from methanol, suctionedoff, and washed with methanol. The filtrate was concentrated byevaporation and a second product fraction was obtained from the residueby column chromatography (CHCl₃:MeOH=9:1).

Yield: 570 mg (1.68 mmol=97% of theory) of colorless crystals

C₁₉H₁₈N₂O₄ [338.37]

TLC: R_(f)=0.60 (CHCl₃:MeOH=9:1)

Melting point: 137-139° C. % C % H % N Cld.: 67.45 5.36 8.28 Fnd.: 67.175.41 8.19

¹H-NMR (200 MHz, CDCl₃): δ 7.09 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.6 Hz,1H), 5.98 (s, 2H), 5.54 (s, 1H), 4.52 (bs, 1H), 4.11 (bs, 1H), 3.83 (s,3H), 3.75-3.59 (m, 1H), 3.42-3.25 (m, 1H), 2.64 (dd, J=15.9, 3.2 Hz,1H), 2.44 (d, J=11.5 Hz, 1H), 2.11-1.94 (m, 2H), 1.71-1.52 (m, 1H);¹³C-NMR (50 MHz, CDCl₃) δ 156.5 (d), 147.1 (s), 145.5 (s), 132.7 (s),129.6 (d), 127.9 (d), 123.8 (s), 120.8 (d), 114.0 (s), 111.7 (d), 88.9(d), 88.6 (s), 68.4 (d), 61.3 (d), 55.9 (q), 52.5 (t), 47.2 (s), 29.3(t), 28.3 (t)

EXAMPLE 125 Step 11-Bromo-5-methoxy-2-(2-methoxyethen-1-yl)-4-(1-methylethoxy)benzene

While being cooled with ice, potassium-tert-butylate (20.5 g, 183 mmol)is added to a suspension of (methoxymethyl)-triphenylphosphoniumchloride (50.0 g, 152 mmol) in absolute THF (330 ml). After 15 minutes,2-bromo-4-methoxy-5-(1-methylethoxy)benzaldehyde (33.1 g, 121 mmol) isadded in portions.

After 15 minutes, the residue that is obtained after the solvent isremoved in a rotary evaporator is dispersed between water (300 ml) andether (300 ml). The organic phase is dried (sodium sulfate), filtered,and the residue that is obtained after concentration by evaporation(37.3 g) is purified by means of MPLC (petroleum ether:ethylacetate=2:1, flow 70 ml/min). In this way, the product is obtained inthe form of colorless crystals (32.5 g, 85%).

Melting point: 43-45° C.

TLC: Petroleum ether:ethyl acetate=2:1 Rf=0.75

¹H: NMR (CDCl₃) δ 7.00 (s, 1H); 6.90 (s, 1H), 6.83 (d, J=12.7 Hz,1H_(trans)), 6.13 (d, J=7.6 Hz, 1H_(cis)), 5.98 (d, J=12.7 Hz,1H_(trans)), 5.50 (d, J=7.6 Hz, 1H_(cis)), 4.49 (septet, J=6.4 Hz, 1H),3.81 (s, 3H), 3.74 (s, 3H_(trans)), 3.70 (s, 3H_(cis)), 1.35 (d, J=6.4Hz, 6H);

¹³C-NMR (CDCl₃) δ 149.2 and 149.6 (s), 147.6 and 148.9 (s), 146.0 and146.7 (d), 127.5 and 128.4 (s), 115.7 and 117.2 (d), 113.6 and 116.2(d), 113.3 and 113.7 (s), 103.8 and 104.2 (d), 71.5 and 71.9 (d), 56.1and 56.4 (q), 56.0 and 60.6 (q), 21.9 and 22.0 (q)

Step 2 2-Bromo-4-methoxy-5-(1-methylethoxy)benzene acetaldehyde

1-Bromo-5-methoxy-2-(2-methoxyethen-1-yl)-4-(1-methylethoxy)benzene(20.0 g, 66.4 mmol) is stirred in tetrahydrofuran (250 ml)/2N Hcl (10ml) for three hours at boiling temperature.

After the solvent is drawn off in a rotary evaporator, the residue isdispersed between water (200 ml) and ether (200 ml), the aqueous phaseis extracted with ether (3×100 ml), the combined organic phases arewashed with water (4×150 ml), saturated sodium bicarbonate solution(2×200 ml) and saturated common salt solution (1×200 ml), dried (sodiumsulfate/activated carbon) and filtered. After concentration byevaporation, the product is obtained as a yellow oil (18.7 g, 98%).

TLC: Petroleum ether:ethyl acetate=4:1, Rf=0.77

¹H: NMR (CDCl₃) δ 9.71 (t, J=1.71 Hz, 1H), 7.06 (s, 1H) 6.80 (s, 1H),4.49 (septet, J=6.4 Hz, 1H), 3.90 (s, 3H), 3.73 (d, J=1.71 Hz, 2H), 1.35(d, J=6.4 Hz, 6H);

¹³C NMR (CDCl₃) δ 191.8 (d), 146.6 (s), 145.1 (s), 125.4 (s) 118.1 (s),115.8 (d), 113.7 (d), 71.5 (d), 56.4 (q), 49.8 (t), 21.8 (q)

Step 3 2-Bromo-4-methoxy-5-(1-methylethoxy)benzene ethanol

2-Bromo-5-(1-methylethoxy)-4-methoxybenzene acetaldehyde (2.60 g, 9.05mmol) is added at 15° C. within 30 minutes to a suspension of sodiumborohydride (0.341 g, 9.05 mmol) in absolute ethanol (40 ml), and it isstirred for two hours at this temperature.

The ethanol is removed in a rotary evaporator, and the residue isdispersed between saturated sodium bicarbonate solution (200 ml) andether (200 ml). The aqueous phase is extracted with ether (3×50 ml). Thecombined organic phases are washed with water (3×200 ml) and saturatedcommon salt solution (1×200 ml), dried (sodium sulfate/activatedcarbon), dried and filtered. After concentration by evaporation, theproduct is obtained in the form of colorless crystals (2.60 g, 99%).

TLC: PE:EE=9:1, 0.25

¹H NMR (CDCl₃) δ 6.98 (s, 1H), 6.80 (s, 1H), 4.47 (septet, J=6.3 Hz,1H), 3.82 (t, J=7.0 Hz, 2H), 3.80 (s, 3H), 2.90 (t, J=7.0 Hz, 2H), 1.32(d, J=7.3 Hz, 6H);

¹³C NMR (CDCl₃) δ 149.7 (s), 146.4 (s), 129.6 (s), 118.5 (d), 116.3 (d),114.8 (s), 71.8 (d), 62.2 (t), 56.1 (q), 38.8 (t), 21.9 (q)

MT-163 JOS 1682

C₂H₇BrO₃ Cld.: C, 49.84; H, 5.93 Fnd.: C, 49.69; H, 5.79

Step 4 1-Bromo-2-(2-iodoethyl)-5-methoxy-4-(1-methylethoxy)benzene

Triphenylphosphine (24.7 g, 94.0 mmol), imidazole (12.8 g, 188.0 mmol)and iodine (23.06 g, 90.9 mmol) are stirred in absolute CH₂Cl₂ (150 ml)for one hour at 15° C.

2-Bromo-5-(1-methylethoxy)-4-methoxybenzene ethanol (18.0 g, 62.2 mmol)in absolute CH₂Cl₂ (100 ml) is added in drops at this temperature within10 minutes, and the mixture is stirred for two hours at roomtemperature.

The mixture is filtered, and the filtrate is washed with water (1×200ml). The aqueous phase is extracted with CH₂Cl₂ (2×50 ml), and thecombined organic phases are washed with sodium thiosulfate solution(1×200 ml), water (1×200 ml), copper sulfate solution (1×200 ml), water(1×200 ml) and saturated common salt solution (1×200 ml), dried (sodiumsulfate/activated carbon), filtered, and the solvent is removed in arotary evaporator.

After purification by column chromatography (1000 g of silicagel/petroleum ether:ethyl acetate=96:4), the product is obtained in theform of colorless needles (19.0 g, 77%).

¹H NMR (CDCl₃) δ 7.00 (s, 1H), 6.77 (s, 1H), 4.49 (septet, J=6.3 Hz,1H), 3.81 (s, 3H), 3.39-3.24 (m, 2H), 3.24-3.09 (m, 2H), 1.36 (d, J=7.3Hz, 6H);

¹³C NMR (CDCl₃) δ 150.0 (s), 146.5 (s), 131.7 (s), 118.0 (d), 116.3 (d),114.3 (s), 71.8 (d), 56.1 (q), 40.0 (t), 22.0 (q), 4.2 (t)

MT 164 JOS 1704

C₁₂H₁₆BrIO₂ Cld.: C, 36.12; H, 4.04 Fnd.: C, 36.38; H, 3.91

Step 52-[2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]ethyl]-propanedioicacid dimethyl ester

1-Bromo-2-(2-iodoethyl)-4-(1-methylethoxy)-5-methoxybenzene (18.0 g,45.1 mmol), potassium carbonate (32.0 g, 321 mmol, anhydrous, freshlyground) and malonic acid dimethyl ester (50.0 g, 378 mmol) are stirredin absolute DMF (200 ml) for 12 hours at 80° C.

The mixture is filtered, the solvent is removed in a rotary evaporator,and the residue is dispersed between water (300 ml) and ether (300 ml).The aqueous phase is extracted with ether (3×50 ml), the combinedorganic phases are washed with water (4×150 ml) and saturated commonsalt solution (1×200 ml), dried (sodium sulfate/activated carbon),filtered, excess malonic ester is removed by distillation from theresidue that is obtained after the solvent is distilled off (160° C./15mbar), and it is purified by means of bulb tube distillation (170°C./0.06 mbar), by which the product is obtained as a colorless oil (18.9g, 72%).

¹H: NMR (CDCl₃) δ 6.99 (s, 1H), 6.73 (s, 1H), 4.49 (septet, J=6.3 Hz,1H), 3.81 (s, 3H), 3.76 (s, 0.6H), 3.39 (t, J=7.9 Hz, 1H), 2.68 (t,J=7.9 Hz, 2H), 2.18 (q, J=7.9 Hz, 2H), 1.34 d, J=6.3 Hz, 6H);

¹³C NMR (CDCl₃) δ 169.6 (s), 149.7 (s), 146.6 (s), 131.7 (s), 117.8 (d),116.3 (d), 114.6 (s), 71.8 (d), 56.2 (q), 52.5 (q), 50.9 (d), 33.1 (t),29.0 (t), 22.0 (q)

MT-165 JOS 1771

C₁₇H₂₃BrO₆ Cld.: C, 50.63; H, 5.75 Fnd.: C, 50.87; H, 5.62

Step 62-[2-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]ethyl]-2-[4-(1-methylethoxy)phenylmethyl]propanedioicacid methyl ester

1-Bromo-2-(2-iodoethyl)-4-(1-methylethoxy)-5-methoxybenzene (18.0 g,45.1 mmol), potassium carbonate (32.0 g, 321 mmol, anhydrous, freshlyground) and (50.0 g, 378.4 mmol) of malonic acid dimethyl ester arestirred (200 ml) in anhydrous DMF for 12 hours at 80° C.

The mixture is filtered, the solvent is drawn off, and the residue isdispersed between 300 ml of water and 300 ml of ether. The aqueous phaseis extracted three times with 50 ml each, the combined organic phasesare washed four times with 150 ml of water each and once with 200 ml ofsaturated common salt solution, dried on sodium sulfate/activatedcarbon, filtered, and the solvent is drawn off. Excess malonic aciddimethyl ester is separated by distillation (160° C./15 mbar), and theresidue is purified by means of bulb tube distillation (170° C. (0.06mbar), by which the product is obtained in the form of a colorless oil(18.9 g, 72%).

MT 166 JOS 1694

C₂₇H₃₅BrO₇ Cld.: C, 58.81; H, 6.40 Fnd.: C, 59.03; H, 6.24

Step 74-[2-Bromo-4-methoxy-5-(1-methylethoxy)]-α-[4-(1-methylethoxy)-phenylmethyl]benzenebutanoicacid

2-[2-[2-Bromo-5-(1-methylethoxy)-4-methoxyphenyl]ethyl]-2-[4-(1-methylethoxy)phenylmethyl]propanedioicacid dimethyl ester (18.1 g, 32.8 mmol) and potassium hydroxide (17.5 g,312 mmol) are stirred in a mixture that consists of ethanol (100 ml) andwater (20 ml) for 12 hours at boiling temperature.

The reaction mixture is acidified with concentrated hydrochloric acid toa pH of 1 and kept under reflux for one hour.

The residue that remains after the solvent is removed is dispersedbetween water (250 ml) and ether (250 ml). The aqueous phase isextracted with ether (2×100 ml), the combined, organic phases are washedneutral with water, washed with saturated common salt solution (150 ml)and dried (sodium sulfate/activated carbon). The residue that remainsafter the solvent is removed is decarboxylated in a bulb tube for 30minutes at 160° C. under high vacuum and then distilled at 210° C./0.008mbar. In this way, the product is obtained in the form of colorlesscrystals (13.3 g, 84%).

¹H: NMR (CDCl₃) δ 7.04 (d, J=9.5 Hz, 2H), 6.99 (s, 1H), 6.80 (d, J=9.5Hz, 2H), 6.77 (s, 1H), 4.60-4.39 (m, 2H), 3.79 (s, 3H), 3.09-2.58 (m,5H), 2.09-1.72 (m, 2H), 1.43-1.29 (m, 1H)

¹³C NMR (CDCl₃): 181.0 (s), 156.2 (s), 149.3 (s), 146.3 (s) 132.3 (s),130.7 (s), 129.6 (d), 117.6 (d), 116.1 (d), 115.7 (d) 114.3 (s), 71.6(d), 69.6 (d), 55.9 (q), 46.7 (d), 37.0 (t), 33.1 (t), 317 (t), 21.8 (q)

Step 84-[2-Bromo-4-methoxy-5-(1-methylethoxy)]-α-[4-(1-methylethoxy)-phenylmethyl]benzenebutanoicacid amide

Oxalic acid dichloride (15 ml) is added in drops at 0° C. within 15minutes to4-[2-bromo-4-methoxy-5-(1-methylethoxy)]-α-[4-(1-methylethoxy)-phenylmethyl]benzenebutanoicacid (24.0 g, 50.1 mmol) in absolute CH₂Cl₂ (200 ml), and the mixture isstirred for two hours at this temperature.

The solvent is removed in a rotary evaporator, the residue is taken upin absolute THF (100 ml), and ammonia is introduced at 0° C. for twohours. The mixture is stirred for one hour at 0° C. and poured ontowater (1000 ml).

The precipitated crystals are filtered off and digested with water(4×500 ml). In this way, the product is obtained in the form ofcolorless crystals (19.9 g, 83%).

¹H NMR (CDCl₃) δ 7.04 (d, J=9.5 Hz, 2H), 6.96 (s, 1H), 6.72 (d, J=9.5Hz, 2H), 6.70 (s, 1H), 6.00 (b, 1H), 5.55 (b, 1H), 4.60-4.30 (m, 2H),3.77 (s, 3H), 2.96-2.52 (m, 4H), 2.51-2.28 (m, 1H), 2.03-1.60 (m, 2H),1.36-1.20 (m, 12H)

¹³C NMR (CDCl₃) 1774, (s), 156.2 (s), 149.2 (s), 146.4 (s) 132.7 (s),131.1 (d), 129.7 (d), 117.5 (s), 116.1 (d), 115.7 (d) 114.4 (d), 71.6(d), 69.6 (d), 56.0 (q), 48.6 (d), 38.0 (t), 33.3 (t), 32.5 (t), 21.9(q).

MT-168 JOS 1770

C₂₄H₃₂BrNO₄ Cld.: C, 60.25; H, 6.74; N, 2.93 Fnd.: C, 60.15; H, 6.55; N,2.77

Step 94-(2-Bromo-5-hydroxy-4-methoxy)-α-(4-hydroxyphenylmethyl)-benzenebutanoicacid amide

Boron trichloride (45 ml, 1.6 M in CH₂Cl₂) is added in drops at −78° C.to4-[2-Bromo-4-methoxy-5-(1-methylethoxy)-α-[4-(1-methylethoxy)-phenylmethyl]benzenebutanoicacid amide (10.0 g, 20.9 mmol) in absolute CH₂Cl₂ (150 ml), and it isstirred for one hour at this temperature. Then, the mixture is heated toroom temperature and stirred for two hours.

It is mixed with water (400 ml), and the organic solvent is distilledoff in a rotary evaporator, whereby the crude product precipitates ascrystals, which is filtered off and is digested with water (6×200 ml)and diisopropyl ether (2×40 ml). In this case, the product is obtainedin the form of colorless crystals (7.11 g, 86%).

MT 171 JOS 1714

C₁₈H₂₀BrNO₄₀0.25H₂O Cld.: C, 54.22; H, 5.18; N, 3.51 Fnd.: C, 54.05; H,4.95; N, 3.54

Step 101-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[h]benzofuran-10-carboxylicacid amide (SPH-1478)

α-[[2-Bromo-5-hydroxy-4-methoxyphenyl]methyl]-4-hydroxybenzenebutanoicacid amide (3.00 g, 7.61 mmol) is suspended in chloroform (300 ml) andmixed with a solution of potassium hexacyanoferrate (III) (13.2 g, 40.0mmol) in potassium carbonate solution (75 ml, ten percent).

The mixture is stirred vigorously at room temperature for 40 minutes andfiltered on Hyflo. The aqueous phase is extracted with chloroform (2×50ml), the combined organic phases are washed with water (2×200 ml) andsaturated common salt solution (1×150 ml), dried (sodium sulfate/silicagel), and the crude product that is obtained after the solvent isconcentrated by evaporation is purified via column chromatography (50 gof silica gel, ethyl acetate). In this way, the product is obtained inthe form of colorless crystals (179 mg, 6%).

TLC: ethyl acetate, R_(f)=0.6

¹H NMR (CDCl₃): δ 6.95 (s, 1H), 6.71 (dd, J=12.1 Hz, J=2.0 Hz, 1H), 6.02(d, J=12.1 Hz, 1H), 5.70 (b, 2H), 4.82 (s, 1H), 3.81 (s, 3H), 3.58 (dd,J=16.5 Hz, J=6.0 Hz, 1H), 3.13 (dd, J=6.0 Hz, J=16.5 Hz, 1H), 2.82-2.57(m, 3H), 2.48-2.15 (m, 2H), 2.12-1.62 (m, 2H);

¹³C NMR (DMSO-d₆): δ 196.7 (s), 178.2 (s), 147.3 (d), 145.6 (s), 143.9(s), 132.5 (s), 131.4 (s), 127.5 (d), 117.0 (s), 114.8 (d), 88.3 (d),53.5 (q), 49.7 (s), 43.7 (d), 40.9 (t), 39.7 (t), 38.0 (t), 32.1 (t);

¹³C NMR (CDCl₃): δ 193.8 (s), 176.7 (s), 146.7 (d), 143.5 (s), 143.2(s), 131.0 (s), 129.9 (s), 127.7 (d), 116.5 (s), 115.1 (d), 87.6 (d),56.1 (q), 49.1 (s), 44.2 (d), 39.4 (t), 37.0 (t), 32.0 (t), 31.7 (t)

EXAMPLE 1261-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-10-carboxylicacid amide (SPH-1479)

L-Selectride^(R) (2.0 ml, 2.0 mmol, 1 M in THF) is added at 0° C. within15 minutes to a suspension of1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-G-oxa-6H-benzoa]cyclohepta[hi]benzofuran-10-carboxylic acid amide (160 mg, 0.41 mmol)in absolute THF (5 ml), and the mixture is stirred for 12 hours at roomtemperature. It is hydrolyzed with water (2 ml) and dispersed betweenwater (10 ml) and ethyl acetate (10 ml), the aqueous phase is extractedwith ethyl acetate (3×5 ml), the combined organic phases are washed with1N hydrochloric acid (3×10 ml), water (2×10 ml), saturated sodiumbicarbonate solution (1×10 ml) and saturated common salt solution (1×10ml), dried (sodium sulfate/activated carbon), filtered, and the crudeproduct that is obtained after the solvent is distilled off is purifiedby means of column chromatography (10 g of silica gel, ethyl acetate).In this way, the product is obtained in the form of colorless crystals(137 mg, 85%).

MT-194 JOS 1712

C₁₈H₂₀BrNO₄ Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.55; H, 5.22; N,3.34

TLC: ethyl acetate, R_(f)=0.5

¹H NMR (MeOH-d₄): δ 6.99 (s, 1H), 6.03 (d, J=16.5 Hz, 1H), 5.94 (dd,J=16.5 Hz, J=5.9 Hz, 1H), 4.52 (s, 1H), 4.16 (s, 1H), 3.76 (s, 3H), 3.49(dd, J=19.8 Hz, J=5.9 Hz, 1H), 2.90 (t, J=17.5 Hz, 1H), 2.77 (t, J=17.5Hz, 1H), 2.46 (d, J=17.6 Hz, 1H), 2.29-2.10 (m, 2H), 1.98-1.53 (m, 3H);

¹³C NMR (MeOH-d₄): δ 181.6 (s), 148.1 (s), 145.4 (s), 135.4 (s), 132.3(s), 129.5 (d), 128.7 (d), 117.8 (d), 115.4 (s), 89.0 (d), 70.3 (d),62.6 (d), 57.2 (q), 45.7 (s), 42.5 (t), 33.5 (t) 33.1 (1), 31.9 (t)

EXAMPLE 127 Step 15-(6-Acetyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

6-Acetyloxyhexanoic acid chloride (16.7 g, 86.6 mmol) in absolute CH₂Cl₂(50 ml) is added in drops at 0° C. within 10 minutes to a suspension ofanhydrous aluminum chloride (61.5 g, 461.6 mmol) in absolute CH₂Cl₂ (500ml), and it is stirred for 15 minutes at this temperature.5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one (10.0 g (57.7 mmol)in absolute CH₂Cl₂ (100 ml) is added in drops within 15 minutes at 0°C., then it is heated to boiling temperature and stirred for 30 minutes.It is cooled to 0° C., hydrolyzed with ice and dispersed between water(300 ml) and CH₂Cl₂ (100 ml). The aqueous phase is extracted with CH₂Cl₂(2×100 ml), the combined organic phases are washed with 2N hydrochloricacid (2×250 ml), water (2×250 ml), semi-concentrated aqueous Na₂CO₃solution (2×250 ml), concentrated aqueous Na₂CO₃ solution (2×250 ml) andconcentrated common salt solution (1×250 ml), dried (sodiumsulfate/activated carbon), and the solvent is removed in a rotaryevaporator.

After recrystallization from methanol (150 ml), the product is obtainedin the form of light yellow crystals (14.3 g, 75.5%).

MT-304 JOS 1675

C₁₉H₂₃NO₄ Cld.: C, 69.28; H, 7.04; N, 4.25 Fnd.: C, 69.27; H, 6.99; N,4.25

¹H NMR (CDCl₃): δ 7.72 (s, 2H), 4.06 (t, J=6.5 Hz, 2H), 3.72 (t, J=5.7Hz, 2H), 3.54 (s, 2H), 2.90 (t, J=7.0 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H),2.09-1.93 (m, 5H), 1.85-1.56 (m, 4H), 1.50-1.30 (m, 2H);

¹³C NMR (CDCl₃): δ 198.9 (s), 174.2 (s), 171.1 (s), 145.5 (s), 131.3(s), 127.8 (d), 122.9 (s), 122.4 (d), 119.5 (s), 64.3 (t), 38.9 (t),38.0 (t), 36.1 (t), 28.5 (t), 25.7 (t), 24.4 (t), 24.1 (t), 21.0 (q),20.9 (t)

Step 25-(6-Hydroxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

5-(6-Acetyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(10.0 g, 30.6 mmol) is suspended in anhydrous ethanol (150 ml), mixedwith catalyst amounts of 4-methylbenzenesulfonic acid monohydrate andstirred for five hours at boiling temperature. The solvent volume isconcentrated by evaporation to one third, and the product is obtained inthe form of light yellow needles (8.22 g, 93.5%) by crystallization at−20° C.

MT-305 JOS 1672

C_(1/)H₂₁NO₃ Cld.: C, 71.06; H, 7.37; N, 4.87 Fnd.: C, 71.30; H, 7.37;N, 4.87

¹H NMR (CDCl₃): δ 7.67 (s, 2H), 3.80-3.52 (m, 4H), 3.48 (s, 2H),2.97-2.66 (m, 4H), 2.08-1.86 (m, 2H), 1.82-1.26 (m, 6H);

¹³C NMR (CDCl₃): δ 199.3 (s), 174.2 (s), 145.4 (s), 131.2 (s), 127.8(d), 122.8 (s), 122.3 (d), 119.4 (s), 62.3 (t), 38.7 (t), 38.0 (t), 36.0(t), 32.3 (t), 25.4 (t), 24.3 (t), 24.1 (t), 20.8 (t)

Step 3 5-(6-Iodo-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

Triphenylphosphine (2.02 g, 7.74 mmol), iodine (3.08 g, 12.12 mmol) andimidazole (0.618 g, 9.08 mmol) are stirred in absolute CH₂Cl₂ (30 ml)for 30 minutes at 15° C.

5-(6-Hydroxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(2.0 g, 6.96 mmol) in anhydrous CH₂Cl₂ (10 ml) is added in drops within5 minutes at this temperature, then it is stirred for 40 minutes at roomtemperature.

It is mixed with semisaturated sodium sulfate solution (50 ml), thephases are separated, the aqueous phase is extracted with CH₂Cl₂, thecombined organic phases are washed with 2N hydrochloric acid (3×100 ml),water (2×100 ml), saturated sodium bicarbonate solution (2×100 ml) andsaturated common salt solution (1×100 ml), dried (sodiumsulfate/activated carbon), filtered, and the crude product that isobtained after the solvent is removed in a rotary evaporator isrecrystallized from methanol (10 ml).

Variant A:

The residue is purified by column chromatography (100 g of silica gel,chloroform), by which the product is obtained in the form of lightyellow crystals (2.44 g, 88.3%).

Variant B:

The residue is recrystallized one additional time from methanol (10 ml),by which the product is obtained in the form of light yellow crystals(2.28 g, 82.4%).

MT-308

JOS 1670 C₁₇H₂₀INO₂ Cld.: C, 51.40; H, 5.07; N, 5.53 Fnd.: C, 51.56; H,4.97; N, 3.46

¹H NMR (CDCl₃): δ 7.70 (s, 2H), 3.72 (t, J=5.7 Hz, 2H), 3.52 (s, 2H),3.18 (t, J=6.9 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H), 2.80 (t, J=6.1 Hz, 2H),2.12-1.61 (m, 6H), 1.57-1.36 (m, 2H);

¹³C NMR (CDCl₃): δ 198.7 (s), 174.1 (s), 145.5 (s), 131.2 (s), 127.8(d), 122.9 (s), 122.3 (d), 119.4 (s), 38.8 (t), 37.9 (t), 36.0 (t), 33.2(t), 30.1 (t), 24.0 (t), 23.3 (t), 20.9 (t), 6.6 (t)

Step 45-(6-Methylsulfonyloxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one

Methanesulfonic acid chloride (458 mg, 4.00 mmol) is added in dropswithin 5 minutes at 15° C. to5-(6-hydroxy-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(1.0 g, 3.48 mmol) and N-ethyldiisopropylamine (560 mg, 4.35 mmol) inanhydrous CH₂Cl₂ (10 ml), and it is then stirred for two hours at roomtemperature.

It is mixed with water (20 ml), the phases are separated, the aqueousphase is extracted with CH₂Cl₂ (1×10 ml), the combined organic phasesare washed with 2N hydrochloric acid (3×10 ml), water (2×10 ml),saturated sodium bicarbonate solution (2×10 ml) and saturated commonsalt solution (1×10 ml), dried (sodium sulfate/activated carbon),filtered, and the crude product that is obtained after the solvent isremoved in a rotary evaporator is digested with diisopropyl ether (10ml), by which the product is obtained in the form of light yellowcrystals (1.17 g, 92.2%).

¹H NMR (CDCl₃): δ 7.70 (s, 2H), 4.22 (t, J=6.5 Hz, 2H), 3.71 (t, J=5.8Hz, 2H), 3.52 (s, 2H), 2.99 (s, 3H), 2.92 (t, J=7.0 Hz, 2H), 2.80 (t,J=6.0 Hz, 2H), 2.17-1.92 (m, 5H), 1.90-1.64 (m, 4H), 1.60-1.37 (m, 2H);

¹³C NMR (CDCl₃): δ 198.7 (s), 174.2 (s), 145.6 (s), 131.2 (s), 127.8(d), 123.0 (s), 122.4 (d), 119.5 (s), 69.8 (t), 38.8 (t), 37.8 (t), 37.3(q), 36.1 (t), 28.9 (t), 25.1 (t), 24.3 (t), 23.7 (t), 20.9 (t)

Step 55-[6-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]-1-oxohexyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2-(1H)-one(SPH-1500)

Norgalanthamine (1.13 g, 1.64 mmol),5-(6-iodo-1-oxohexyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-one(1.50 g, 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3 mmol) arestirred in absolute chloroform (20 ml) for 54 hours at boilingtemperature.

The residue that is obtained after the solvent is removed in a rotaryevaporator is purified by column chromatography (200 g of silica gel,chloroform:methanol:ammonia=96:3:1), by which the product is obtained asa light yellow foam (1.31 g, 64.3%).

¹H NMR (CDCl₃): δ 7.63 (s, 2H), 6.68-6.46 (m, 2H), 6.00 (d, J=10.3 Hz,1H), 5.90 (dd, J=10.3 Hz, J=4.6 Hz, 1H), 4.51 (s, 1H), 4.19-3.96 (m,2H), 3.75 (s, 1H), 3.73 (s, 3H), 3.70-3.58 (m, 2H), 3.44 (s, 2H),3.35-2.98 (m, 2H), 2.96-6.67 (m, 4H), 2.66-2.29 (m, 4H), 2.15-1.84 (m,4H), 1.82-1.11 (m, 6H);

¹³C NMR (CDCl₃): δ 199.1 (s), 174.1 (s), 145.6 (s), 145.3 (s), 143.8(s), 133.0 (s), 131.2 (s), 129.3 (s), 127.7 (d), 127.4 (d), 126.8 (d),122.8 (s), 122.3 (d), 121.7 (d), 119.4 (s), 111.0 (d), 88.5 (d), 61.8(d), 57.6 (t), 55.7 (q), 51.4 (t), 51.2 (t), 48.2 (s), 38.7 (t), 38.0(t), 36.0 (t), 32.8 (t), 29.8 (t), 27.1 (t), 26.9 (t), 24.3 (t), 24.2(t), 20.8 (t),

Step 65-[6-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]-1-oxohexyl]-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-2(1H)-onefumarate (SPH-1499)

The precipitation of the fumarate was carried out analogously to Example4.

MT-311 JOS 1762

C₃₇H₄₂N₂O₉*H₂O Cld.: C, 65.67; H, 6.55; N, 4.14 Fnd.: C, 65.93; H, 6.54;N, 4.03

EXAMPLE 128a Step 1 2-[[4-(1-Methylethoxy)phenyl]methyl]propanedioicacid dimethyl ester

1-(Chloromethyl)-4-(1-methylethoxy)benzene (20.5 g, 111 mmol), malonicacid dimethyl ester (102.5 g, 776 mmol) and potassium carbonate (46.5 g,332 mmol, anhydrous, freshly ground) are stirred in absolute DMF (250ml) for 24 hours at 70° C.

The mixture is filtered, and the residue that is obtained after thefiltrate is concentrated by evaporation in a rotary evaporator isdispersed between ether (250 ml) and water (250 ml). The organic phaseis washed with water (3×200 ml) and saturated common salt solution(1×200 ml), dried (sodium sulfate/activated carbon), filtered, and thesolvent is removed.

The excess malonic acid dimethyl ester is separated by vacuumdistillation (85° C./15 mbar), and the crude product that remains in theresidue is purified by bulb tube distillation (130° C./0.001 mbar). Inthis way, the product is obtained as a colorless oil (23.6 g, 78%).

MT-67 JOS 1774

C₁₅H₂₀O₅ Cld.: C, 64.27; H, 7.19 Fnd.: C, 64.28; H, 7.07

Step 2 4-(1-Methylethoxy)benzenepropanoic acid

2-[[4-(1-Methylethoxy)phenyl]methyl]-propanedioic acid dimethyl ester(23.6 g, 84.2 mmol) is stirred into 2N potassium hydroxide solution (15ml)/ethanol (25 ml) for 18 hours at boiling temperature.

The ethanol is distilled off in a rotary evaporator, the residue isbrought to a pH of 1 with concentrated hydrochloric acid and extractedwith ether (3×150 ml). The combined organic phases are washed with water(6×200 ml) and saturated common salt solution (200 ml), dried (sodiumsulfate/activated carbon) and filtered. The residue that is obtainedafter concentration by evaporation in a rotary evaporator isdecarboxylated in a bulb tube (140° C./0.08 mbar) and then distilled(155° C./0.08 mbar) In this way, the product is obtained in the form ofcolorless crystals (14.4 g, 82%).

¹H NMR (CDCl₃): δ 7.12 (d, J=9.5 Hz, 2H), 6.82 (d, J=9.5 Hz, 2H), 4.50(septet, J=6.3 Hz, 1H), 2.89 (t, J=7.9 Hz, 2H), 2.63 (t, J=7.9 Hz, 2H),1.32 (d, J=6.3 Hz, 6H);

¹³C NMR (CDCl₃): δ 178.8 (s), 156.4 (s), 132.1 (s), 129.2 (d), 116.0(d), 69.9 (d), 35.8 (t), 29.7 (t), 22.1 (q)

Step 3 2-Bromo-4-methoxy-5-(1-methylethoxy)benzene acetonitrile

1-Bromo-2-(chloromethyl)-5-methoxy-4-(1-methylethoxy)benzene (7.00 g,23.8 mmol) and potassium cyanide (1.70 g, 26.1 mmol, freshly ground) arestirred in absolute DMSO (70 ml) for 12 hours at room temperature.

The mixture is poured onto water (700 ml), the aqueous phase isextracted with ether (3×150 ml), the combined organic phases are washedwith water (5×150 ml) and saturated common salt solution (1×200 ml),dried (sodium sulfate/activated carbon), filtered, and the residue thatis obtained after concentration by evaporation is digested withdiisopropyl ether (15 ml). In this way, the product is obtained in theform of colorless crystals (6.46 g, 95%).

MT-72 JOS 1695

C₁₂H₁₄BrNO₂ Cld.: C, 50.72; H, 4.97; N, 4.93 Fnd.: C, 50.73; H, 4.84; N,4.89

¹H NMR (CDCl₃): δ 7.02 (s, 1H), 6.97 (s, 1H), 4.50 (septet, J=6.3 Hz,1H), 3.81 (s, 3H), 3.72 (s, 2H), 1.36 (d, J=6.3 Hz, 6H);

¹³C NMR (CDCl₃): δ 150.8 (s), 147.1 (s), 12.1 5 (s), 117.3 (s), 116.7(d), 116.3 (d), 113.9 (s), 72.1 (d) 56.2 (q), 24.2 (t), 21.9 (q)

Step 4 4-(1-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl ester

4-Hydroxybenzenepropanoic acid (50.0 g, 300 mmol), potassium carbonate(210 g, 1.5 mol, anhydrous, freshly ground) and 2-bromopropane (221 g,1.8 mol) are stirred in absolute DMF (500 ml) for 24 hours at 60° C.

The solution is filtered, and the residue that is obtained after theconcentration by evaporation in a rotary evaporator is dispersed betweenether (500 ml) and 2N sodium hydroxide solution (500 ml). The organicphase is washed with 2N sodium hydroxide solution (2×200 ml), water(3×500 ml) and saturated common salt solution (200 ml), dried (sodiumsulfate/activated carbon) and filtered. The residue that is obtainedafter the solvent is distilled off in a rotary evaporator is purified bybulb tube distillation (139-142° C./0.025 mbar), by which the product isobtained as a colorless oil (70.8 g, 94%).

MT-159 JOS 1768

C₁₅H₂₂O₃ Cld.: C, 71.97; H, 8.86 Fnd.: C, 71.84; H, 8.75

¹H NMR (CDCl₃) δ 7.10 (d, J=9.5 Hz, 2H), 6.81 (d, J=9.5 Hz, 2H), 4.99(septet, J=6.2 Hz, 1H), 4.48 (septet, J=6.3 Hz, 1H), 2.87 (t, J=7.9 Hz,2H), 2.54 (t, J=7.9 Hz, 2H), 1.20 (d, J=6.3 Hz, 6H), 1.31 (d, J=6.3 Hz,6H);

¹³C NMR (CDCl₃): δ 172.4 (s), 156.2 (s), 132.4 (s), 129.1 (d), 115.8(d), 69.7 (d), 67.4 (d), 36.4 (t), 30.1 (t), 22.0 (q), 21.7 (q)

Step 5 4-(1-Methylethoxy)benzenepropanol 1. From4-(1-methylethoxy)benzenepropanoic acid

4-(1-Methylethoxy)benzenepropanoic acid (7.57 g, 36.3 mmol) in absoluteTHF (80 ml) is added in drops at 0° C. to a suspension of lithiumaluminum hydride (4.17 g, 110 mmol) in absolute THF (80 ml) within 30minutes, and it is stirred for 12 hours at room temperature. It ishydrolyzed with water (30 ml) and mixed with concentrated hydrochloricacid until the solution becomes clear, dispersed between water (30 ml)and ether (60 ml), the aqueous phase is extracted with ether (2×20 ml),the combined organic phases are washed with 2N hydrochloric acid (3×100ml), water (1×100 ml), saturated sodium bicarbonate solution (2×100 ml)and saturated common salt solution (1×100 ml), dried (sodiumsulfate/activated carbon) and filtered. After the solvent is distilledoff in a rotary evaporator, the product is obtained in the form ofcolorless crystals (6.84 g, 97%)

2. From 4-(1-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl ester

4-(1-Methylethoxy)benzenepropanoic acid-(1-methyl)ethyl ester (10.0 g,39.9 mmol) in absolute THF (100 ml) is added in drops at 0° C. to asuspension of lithium aluminum hydride (3.04 g, 80 mmol) in absolute THF(100 ml) within 30 minutes, and it is stirred for 12 hours at roomtemperature.

It is hydrolyzed with water (30 ml) and mixed with concentratedhydrochloric acid, until the solution becomes clear, dispersed betweenwater (30 ml) and ether (60 ml), the aqueous phase is extracted withether (2×20 ml), the combined organic phases are washed with 2Nhydrochloric acid (3×100 ml), water (1×100 ml), saturated sodiumbicarbonate solution (2×100 ml) and saturated common salt solution(1×100 ml), dried (sodium sulfate/activated carbon) and filtered.

After the solvent is distilled off in a rotary evaporator, the productis obtained in the form of colorless crystals (7.04 g, 99%).

MT-89 JOS 1700

C₁₂H₁₈O₂ Cld.: C, 74.19; H, 9.34 Fnd.: C, 73.93; H, 9.07

¹H NMR (CDCl₃): δ 7.10 (d, J=9.5 Hz, 2H), 6.82 (d, J=9.5 Hz, 2H), 4.50(septet, J=6.3 Hz, 1H), 3.68 (t, J=7.9 Hz, 2H), 2.66 (t, J=7.9 Hz, 2H),2.0 (b, 1H), 1.93-1.78 (m, 2H), 1.32 (d, J=6.3 Hz, 6H);

¹³C NMR (CDCl₃): δ 155.9 (s), 133.7 (s), 129.2 (d), 115.9 (d), 69.9 (d),62.0 (t), 34.3 (t), 31.1 (t), 22.0 (q)

Step 6 1-(3-Iodopropyl)-4-(1-methylethoxy)benzene

Triphenylphosphine (13.1 g, 49.9 mmol), iodine (19.9 g, 78.4 mmol) andimidazole (4.0 g, 58.8 mmol) are stirred in absolute CH₂Cl₂ (250 ml) for20 minutes at room temperature. 4-(1-Methylethoxy)benzenepropanol (8.74g, 45.0 mmol) in CH₂Cl₂ (100 ml) is added in drops at 15° C. and stirredfor 12 hours at room temperature.

It is dispersed between water (300 ml) and CH₂Cl₂ (150 ml), the aqueousphase is extracted with CH₂Cl₂ (2×50 ml), the combined organic phasesare washed with water (1×200 ml), semisaturated copper(II) sulfatesolution (2×200 ml), water (1×200 ml), 10% sodium sulfite solution(1×200 ml), saturated common salt solution (1×200 ml), dried (sodiumsulfate/activated carbon), filtered, and the residue that is obtainedafter concentration by evaporation in a rotary evaporator is taken up indiisopropyl ether (200 ml). The residue that is obtained from thefiltrate after the solvent is drawn off in a rotary evaporator isfiltered and purified by column chromatography (900 g of silica gel;petroleum ether ethyl acetate=95:5). In this way, the product isobtained as a colorless oil (10.9 g, 79%).

MT-151 JOS 1755

C₁₂H₁₇IO Cld.: C, 47.39; H, 5.63 Fnd.: C, 47.37; H, 5.41

¹H NMR (CDCl₃): δ 7.11 (d, J=9.5 Hz, 2H), 6.82 (d, J=9.5 Hz, 2H), 4.53(septet, J=6.3 Hz, 1H), 3.18 (t, J=7.9 Hz, 2H), 2.67 (t, J=7.9 Hz, 2H),2.10 (quintet, J=7.9 Hz, 2H), 1.35 (d, J=6.3 Hz, 6H);

¹³C NMR (CDCl₃): δ 156.2 (s), 132.2 (s), 129.4 (d), 115.9 (d), 69.8 (d),35.2 (t), 35.0 (t), 22.1 (q), 6.5 (t)

Step 7α-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]4-(1-methylethoxy)-benzenepentanenitrile

n-Butyllithium (12.7 ml, 27.5 mmol, 2.2 M in hexane) is added within 15minutes at a temperature of −78° C. to a solution of diisopropylamine(3.55 g, 35.08 mmol) in absolute THF (50 ml), then the mixture is heatedto −30° C. and stirred for 30 minutes at this temperature.

The solution is cooled to −78° C., mixed with2-bromo-4-methoxy-5-(1-methylethoxy)-benzene acetonitrile (7.94 g, 27.9mmol) in absolute THF (100 ml), stirred for 20 minutes at thistemperature, heated to room temperature, and stirred for another hour.The mixture is cooled to −78° C., then 1(3-iodopropyl)-4-(1-methylethoxy)benzene (8.50 g, 27.9 mmol) in absoluteTHF (50 ml) is added in drops with 15 minutes, and the mixture isstirred for 45 minutes.

It is mixed with saturated ammonium chloride solution (50 ml) and heatedto room temperature. The residue that is obtained after concentration byevaporation is dispersed between 2N hydrochloric acid (200 ml) and ether(200 ml). The aqueous phase is extracted with ether (3×50 ml), thecombined organic phases are washed with water (3×200 ml), saturatedsodium bicarbonate solution (1×200 ml) and saturated common saltsolution (1×200 ml), dried (sodium sulfate/activated carbon), filtered,and the residue that remains after the solvent is removed in a rotaryevaporator is purified by column chromatography (1000 g of silica gel,petroleum ether:ethyl acetate=98:2). The product is thus obtained as acolorless oil (11.46 g, 71%).

MT-158 JOS 1699

C₂₄H₃₀BrNO₃ Cld.: C, 62.61; H, 6.57; N, 3.04 Fnd.: C, 62.32; H, 6.21; N,2.97

Step 8α-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylethoxy)-benzenepentanoic acid amide

α-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylethoxy)benzenepentane nitrile (30.0 g, 65.2 mmol) in ethanol (600 ml) is mixed withpotassium hydroxide (60.0 g, 1.07 mol) in water (100 ml) and stirred for6 hours at boiling temperature.

The residue that is obtained after concentration by evaporation isdispersed between 2N hydrochloric acid (200 ml) and ether (300 ml). Theaqueous phase is extracted with ether (3×75 ml). The combined organicphases are washed with water (3×200 ml), saturated sodium bicarbonatesolution (1×200 ml) and saturated common salt solution (1×200 ml), dried(sodium sulfate/activated carbon), filtered, and the residue thatremains after the solvent is removed is purified by columnchromatography (1000 g of silica gel, petroleum ether:ether=1:2). Thehigher-running fraction is taken up in absolute CH₂Cl₂ (100 ml), mixedat 0° C. with oxalic acid chloride (3 ml) and a drop of DMF and stirredfor two hours. The residue that is obtained after the solvent is drawnoff in a rotary evaporator is suspended in absolute THF (100 ml),whereupon ammonia is introduced under the surface for two hours. Themixture is filtered, and the residue that is obtained afterconcentration by evaporation is dispersed between water (100 ml) andether (100 ml). The aqueous phase is extracted with ether (3×50 ml), thecombined organic phases are washed with water (3×200 ml) and saturatedcommon salt solution (1×200 ml), dried (sodium sulfate/activatedcarbon), filtered, and the residue that is obtained after concentrationby evaporation is combined with the deeper-running fraction that isobtained by column chromatography, crystallized under diisopropyl etherand digested with diisopropyl ether (100 ml). In this way, the productis obtained in the form of colorless crystals (26.0 g, 83.5%).

¹H NMR (CDCl₃): δ 7.01 (d, J=8.9 Hz, 2H), 6.98 (s, 1H), 6.92 (s, 1H),6.75 (d, J=8.9 Hz, 2H), 5.98 (b, 1H), 5.52 (b, 1H), 4.47 (septet, J=6.3Hz, 2H), 3.91 (t, J=7.0 Hz, 1H), 3.82 (s, 3H), 2.74-2.40 (m, 2H),2.22-2.00 (m, 1H), 1.91-1.36 (m, 3H), 1.35-1.22 (m, 6H);

¹³C NMR (CDCl₃): δ 175.2 (s), 155.8 (s), 149.9 (s), 147.0 (s), 133.9(s), 130.8 (s), 129.1 (d), 115.7 (d), 114.8 (d), 114.7 (d), 71.4 (d),69.7 (d), 56.0 (g), 49.7 (d), 34.6 (t), 31.9 (t) 29.1 (t), 22.0 (q) 21.8(q), 21.7 (q)

Step 9 α-[2-Bromo-5-hydroxy-4-methoxyphenyl]-4-hydroxybenzenepentanoicacid amide

α-[2-Bromo-4-methoxy-5-(1-methylethoxy)phenyl]-4-(1-methylethoxy)benzenepentanoicacid amide (24.0 g, 50.2 mmol) in absolute CH₂Cl₂ (300 ml) is mixed at−78° C. with boron trichloride (150 ml, 150 mmol, 1 M in CH₂Cl₂) andstirred for four hours at room temperature.

Water (200 ml) is added in drops, and the organic phase is removed in arotary evaporator. The precipitated crystals are digested with water(6×200 ml), by which the product is obtained in the form of colorlesscrystals (19.8 g, quant.).

MT-161 JOS 1713

C₁₈H₂₀BrNO₄ Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.56; H, 5.40; N,3.25

Step 101-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi]benzofuran-12-carboxylicacid amide (SPH-1484)

α-[2-Bromo-5-hydroxy-4-methoxyphenyl)-5-hydroxybenzenepentanoic acidamide (3.00 g, 7.61 mmol) is suspended in chloroform (300 ml) and mixedwith a solution of potassium hexacyanoferrate (III) (13.2 g, 40.0 mmol)in potassium carbonate solution (75 ml, ten percent).

The mixture is vigorously stirred at room temperature for 40 minutes andfiltered on Hyflo. The aqueous phase is extracted with chloroform (2×50ml), the combined organic phases are washed with 2N hydrochloric acid(2×100 ml), water (2×200 ml) and saturated common salt solution (1×150ml), dried (sodium sulfate/activated carbon), and the crude product thatis obtained after concentration by evaporation of the solvent ispurified via column chromatography (50 g of silica gel, ethyl acetate).In this way, the product is obtained as a mixture that consists of twodiastereomeric enantiomer pairs, whereby the deeper-running isisomerized to the higher-running.

By column chromatography (chloroform methanol 96:4), the enantiomer pairwith the higher Rf-value is obtained in the form of colorless crystals(0.24 g, 8% of theory).

MT-162/OF JOS 1679

C₁₈H₁₈BrNO₄ Cld.: C, 55.12; H, 4.63; N, 3.57 Fnd.: C, 55.15; H, 4.71; N,3.38

¹H NMR (DMSO-d₆): δ 7.57 (, 1H), 7.48 (d, J=14.5 Hz, 1H), 7.14 (s, 2H),5.89 (d, J=14.5 Hz, 1H), 4.66 (s, 1H), 4.32 (s, 1H), 4.01 (q, J=7.7 Hz,1H), 3.78 (s, 3H), 3.02 (d, J=19.6 Hz, 1H), 2.79 (d, J=19.6 Hz, 1H),2.52 (d, J=16.5 Hz, 1H), 2.16 (d, J=16.5 Hz, 1H), 1.96-1.67 (m, 2H),1.14 (t, J=7.7 Hz, 1H)

¹³C NMR (DMSO-d₆): δ 195.6 (s), 174.6 (s), 149.5 (d), 147.9 (s), 144.4(s), 133.6 (s), 130.6 (s), 126.5 (d), 117.5 (s), 117.1 (d), 88.4 (d),56.8 (q), 52.1 (s), 51.6 (d), 37.9 (t), 36.6 (t), 33.3 (t), 21.5 (t)

EXAMPLE 128b(6R)-1-Bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-12-carboxylicacid amide (SPH-483)

L-Selectride® (4.6 ml, 4.6 mmol, 1. M in THF) is added at 0° C. within15 minutes to a suspension of1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-oxa-6H-benzo[a]cyclohepta[hi]benzofuran-12-carboxylicacid amide (600 mg, 1.52 mmol) in absolute THF (5 ml), and the mixtureis stirred for 12 hours at room temperature. It is hydrolyzed with water(3 ml) and dispersed between water (10 ml) and ethyl acetate (10 ml),the aqueous phase is extracted with ethyl acetate (3×5 ml), the combinedorganic phases are washed with 1N hydrochloric acid (3×10 ml), water(2×10 ml), saturated sodium bicarbonate solution (1×10 ml) and saturatedcommon salt solution (1×10 ml), dried (sodium sulfate/activated carbon),filtered, and the crude product that is obtained after the solvent isdistilled off is purified by means of column chromatography (50 g ofsilica gel, ethyl acetate). In this way, the product is obtained in theform of colorless crystals (798 mg, 83%).

MT-169/OF JOS 1677

C₁₈H₂₀BrNO₄ Cld.: C, 54.84; H, 5.11; N, 3.55 Fnd.: C, 54.67; H, 5.10; N,3.46

¹H NMR (CDCl₃/DMSO-d₆): δ 6.97 (s, 1H), 6.79 (b, 1H), 6.49 (b, 1H), 6.12(d, J=11.4 Hz, 1H), 5.83 (dd, J=11.4 Hz, J=5.1 Hz, 1H), 4.42 (s, 1H),4.31-4.21 (m, 1H), 3.78 (s, 3H), 3.42-3.18 (m, 2H), 2.68-2.29 (m, 2H),2.14-1.38 (m, 5H);

¹³C NMR (CDCl₃/DMSO-d₆): δ 173.4 (s), 146.3 (s), 143.6 (s) 134.2 (s),128.8 (d), 128.6 (d), 126.8 (s), 116.1 (s), 115.6 (d), 87.1 (d), 60.1(q), 55.6 (d), 50.1 (s), 49.5 (d), 37.5 (t), 31.0 (t); 29.8 (t), 20.3(t)

EXAMPLE 128c(6R)-10-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol(SPH-1482)

Bis(trifluoroacetoxy)iodobenzene (300 mg, 0.76 mmol) is dissolved inacetonitrile (1.5 ml, HPLC-quality) and mixed with water (1.5 ml,HPLC-quality). Then,(6R)-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-12-carboxylicacid amide (338 mg, 0.76 mmol) is added in substance within 2 hours, andthe mixture is stirred for 24 hours at room temperature. The solvent isdistilled off in a rotary evaporator, the residue is taken up inchloroform (5 ml), filtered and purified by column chromatography (30 gof silica gel, chloroform:methanol:ammonia=96:3:1). In this way, theproduct is obtained in the form of colorless crystals (161 mg, 58%).

MT-170 JOS 1705

C₁₇H₂₀BrNO₃.0.66H₂O Cld.: C, 54.02; H, 5.68; N, 3.71 Fnd.: C, 53.96; H,5.52; N, 3.60

¹H NMR (MeOH-d₄): δ 7.08 (s, 1H), 6.41 (d, J=14.5 Hz, 1H), 5.8883 (dd,J=14.5 Hz, J=5.1 Hz, 1H); 4.72 (s, 1H), 4.58 (s, 1H), 4.13 (t, J=3.6 Hz,1H), 3.82 (s, 3H), 2.49 (d, J=17.2 Hz, 1H), 2.45-2.07 (m, 4H), 1.92-1.58(m, 4H);

¹³C NMR (MeOH-d₄): δ 147.2 (s), 144.7 (s), 134.5 (s), 133.3 (s), 130.9(d), 126.4 (d), 116.6 (d), 115.5 (s), 87.8 (d), 61.2 (d), 57.3 (q), 54.0(d), 48.6 (s), 38.3 (t), 35.2 (t), 30.1 (t) 17.9 (t)

EXAMPLE 128d(6R)-10-Amino-4a,59,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzoa]cyclohepta[hi]benzofuran-6-ol

(6R)-10-Amino-1-bromo-4a,5,9,10,11,12-hexahydro-3-methoxy-6-hydroxy-6H-benzo[a]cyclohepta[hi]benzofuran-6-ol(70 mg, 0.19 mmol) and calcium chloride (300 mg, 2.7 mmol) are added insubstance to a black suspension of zinc (production: zinc powder (500mg) and copper(I) iodide (500 mg) are treated under argon in water (4ml) and ethanol (4 ml) for 45 minutes in an ultrasound bath), and themixture is stirred for 5 hours at boiling temperature. It is mixed withconcentrated aqueous ammonia solution (1 ml), the solvent is removed ina rotary evaporator, the residue is taken up in chloroform (15 ml),filtered, and the residue that is obtained after the filtrate isconcentrated by evaporation in a rotary evaporator is purified by columnchromatography (30 g of silica gel, chloroform methanol ammonia=96:3:1).In this way, the product is obtained in the form of colorless crystals(42 mg, 78%).

¹H NMR (CDCl₃): δ 6.81-6.61 (m, 3H), 6.97 (dd, J=14 Hz, J=4 Hz, 1H),4.44 (s, 1H), 4.30 (s, 1H), 4.24 (t, J=3 Hz, 1H), 3.85 (s, 3H), 2.63(dd, J=17 Hz, J=6 Hz, 1H), 2.40 (q, J=15 Hz, 1H), 2.19-2.08 (m, 1H),2.02 (dd, J=18 Hz, J=4 Hz, 1H), 1.97-1.52 (m, 9H)

¹³C NMR (CDCl₃): δ 145.4 (s), 143.2 (s), 134.1 (s), 132.6 (s), 129.9(d), 125.4 (d), 121.9 (d), 109.9 (d), 87.7 (d), 61.1 (d), 54.8 (q), 48.5(s), 37.0 (t), 34.4 (t), 29.0 (t), 25.8 (t), 16.9 (t)

EXAMPLE 1298-[6-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]-1-oxohexyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(SPH-1516)

1. Synthesis in Solution:

Norgalanthamine (1.13 g, 4.13 mmol),8-(6-iodo-1-oxohexyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one(1.50 g, 3.75 mmol) and N-ethyldiisopropylamine (1.46 g, 11.3 mmol) arestirred in absolute chloroform (20 ml) for 54 hours at boilingtemperature.

The residue that is obtained after the solvent is removed in a rotaryevaporator is purified by column chromatography (200 g of silica gel,chloroform:methanol: ammonia 96:3:1), by which the product is obtainedas a light yellow foam (1.87 g, 92%).

TLC: CHCl₃:MeOH:NH₃=89:10:1, R_(f)=0.5

¹H NMR (CDCl₃): δ 7.62 (s, 1H), 7.67 (s, 1H), 6.68-6.43 (m, 2H), 6.00(d, J=9.7 Hz, 1H), 5.93-5.81 (m, 1H), 4.51 (s, 1H), 4.22-3.91 (m, 4H),3.92-3.64 (m, 4H), 3.48-2.28 (m, 13H), 2.20-1.12 (m, 10H);

¹³C NMR (CDCl₃): δ 198.7 (s), 167.5 (s), 145.5 (s), 145.1 (s), 143.7(s), 132.8 (s), 132.6 (s), 129.1 (s), 128.9 (s), 127.2 (d), 126.7 (d),126.3 (d), 123.6 (d), 121.6 (d), 119.3 (s), 110.8 (d), 88.3 (d), 61.6(d), 57.4 (t), 55.6 (q), 51.2 (t), 51.0 (t), 48.1 (s), 45.4 (t), 38.0(t), 32.6 (t), 31.1 (t), 29.7 (t), 27.0 (t), 26.8 (t), 24.2 (t), 23.9(t)

Production of Fumarate (SPH-1519) Analogously to Example 4

MT-407 JOS 1761

C₃₇H₄₂N₂O₂*H₂O Cld.: C, 65.67; H, 6.55; N, 4.14 Fnd.: C, 65.69; H, 6.49;N, 4.022. By Solid-Phase Synthesis

0.300 g (0.102 mmol) ofnorgalanthamine-6-yloxy)-1,5-dioxopentyloxymethyl-Merrifield resin issteeped in a 5-ml-polyethylene frit that is sealed on both sides for 30minutes in 3 ml of dimethylformamide/acetone (1/1) and after filtering,it is suspended in a solution of 0.125 g (0.315 mmol) of8-(6-iodo-1-oxohexyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-4-oneand 54 μl (0.041 g, 0.315 mmol) of ethyldiisopropylamine in 3 ml ofdimethylformamide/acetone (1/1).

The suspension is shaken at room temperature for 19 hours. A negativechloranil test indicates the complete conversion of the secondary amine.The resin is washed three times with dimethylformamide (2 minutes, 3 ml)and six times with tetrahydrofuran/methanol (4/1, 2 minutes, 3 ml). Theresin is suspended below in a solution that consists of 0.113 g (0.63mmol) of 30% sodium methanolate-methanol solution and 3.0 ml oftetrahydrofuran/methanol (4/1). After 15 hours, the solution is filteredoff, and the resin is extracted six times with 3 ml each ofdichloromethane.

The combined filtrates are neutralized with methanolic hydrochloricacid, diluted with 10 ml of dichloromethane, washed twice with 15 ml ofsaturated sodium chloride solution, dried on sodium sulfate, filteredand concentrated by evaporation in a rotary evaporator under reducedpressure. The crude product is separated by means of MPLC (200 g ofsilica gel, v=285 nm, chloroform/methanol/concentrated ammonia=96/3/1).After the concentration by evaporation, a yellow oil that crystallizeswhile standing is obtained: 0.043 g (0.041 g, 0.075 mmol, 74%) ofyellowish crystals (M_(w)=542.7), HPLC, TLC identical to a referencesample:

TLC: R_(f)=0.55 (chloroform/methanol=8/2+2% concentrated ammonia)

HPLC: t_(Ref)=13.7 minutes, 95.7% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5.0 μm, 1 ml/min, 285 nm, acetonitrile/20 mmol of Cl₃CCO₂Hin H₂O (5/95 v/v for 5 minutes, 5/95→60/40 v/v in 18 minutes (convex),60/40 vv for 5 minutes)

EXAMPLE 130a(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,galanthamine (HM 424)

Lithium aluminum hydride (104 mg, 2.73 mmol) was added to a suspensionof galanthaminium bromide HM 407 (1.0 g, 2.73 mmol) in absolutetetrahydrofuran (50 ml) and stirred for 3 hours at room temperature.Then, excess lithium aluminum hydride, annihilated with ethyl acetate,was added to water (49 mg, 2.73 mmol) to form a precipitate that couldbe filtered, and precipitated. The Al₂O₃ that was produced was filteredoff, the filtrate was dried on sodium sulfate, and the solvent wasremoved in Rotavapor. 750 mg (96% of theory) of galanthamine wasobtained as a white foam.

TLC: CHCl₃:MeOH/NH₃ (9:1)

¹H NMR (CDCl₃): δ 6.66-6.58 (m, 2H), 6.08-5.94 (m, 2H), 4.58 (b, 1H),4.15 (b, 1H), 4.06 (d, J=15.2 Hz, 1H), 3.78 (s, 3H), 3.66 (d, J=15.2 Hz,1H), 3.25 (ddd, J=14.4, 2.2, 1.9 Hz, 1H), 3.05 (ddd, J=14.9, 3.1, 3.1Hz, 1H), 2.68 (ddd, J=15.7, 1.8, 1.8, 1H), 2.40 (s, 3H), 2.15-1.90 (m,2H), 1.55 (ddd, J=13.7, 4.1, 2.0 Hz, 1H); ¹³C NMR (CDCl₃): δ 145.8 (s),144.1 (s), 133.1 (s), 129.2 (s), 127.6 (d), 126.8 (d), 122.1 (d), 111.1(d), 88.7 (d), 62.0 (d), 60.4 (t), 55.8 (q), 53.7 (t), 48.2 (s), 41.9(q) 33.4 (t), 29.9 (t)

EXAMPLE 130b(4aS,6R,8aS)-4a,5,9,10,11-Pentahydro-12-deutero-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,(12-deuterogalanthamine, SPH-1520)

Lithium aluminum deuteride (28 mg, 0.68 mmol) was added to a suspensionof galanthaminium bromide HM 407 (250 mg, 0.683 mmol) in absolutetetrahydrofuran (15 ml) and stirred for 3 hours at room temperature.Then, excess lithium aluminum deuteride was destroyed with ethyl acetateand precipitated with deuterium oxide (12 mg, 0.68 mmol) of Al₂O₃ TheAl₂O₃ that was produced was filtered off, the filtrate was dried onsodium sulfate, and the solvent was removed in Rotavapor. 100 mg (51% oftheory) of HM 427 was obtained as a white foam.

TLC: CHCl₃:MeOH/NH₃ (9:1)

¹H NMR (CDCl₃): δ 6.66-6.58 (m, 2H), 6.08-5.94 (m, 2H), 4.58 (b, 1H),4.14 (b, 1H), 4.06 (d, J=15.2 Hz, 0.5H), 3.78 (s, 3H), 3.66 (d, J=15.2Hz, 0.5H), 3.25 (ddd, J=14.4, 2.2, 1.9 Hz, 1H), 3.05 (ddd, J=14.9, 3.1,3.1 Hz, 1H), 2.68, (ddd, J=15.7, 1.8, 1.8, 1H), 2.40 (s, 3H), 2.15-1.90(m, 2H), 1.55 (ddd, J=13.7, 4.1, 2.0 Hz, 1H); ¹³C NMR (CDCl₃): δ 145.8(s), 144.1 (s) 133.1 (s), 129.2 (s), 127.6 (d), 126.8 (d), 122.1 and122.0 (d), 111.1 (d), 88.7 (d), 62.0 (d), 60.4 (t), 55.8 (q), 53.8 and53.7 (t), 48.2 (s), 42.1 and 4.1.9 (q), 33.8 and 33.7 (t), 29.9 (t)

LC/MS:30*2.1 mm of Zorbax SB C18 3 μm, 40% MeOH for 2 minutes to 100% @10 minutes for 10 minutes; remainder of H2O at 0.5 ml/minute, UV 210,250, 280 and 310 nm, a single peak (RT about 6.0 minutes). PI-MS m/z 289([M+H]⁺), 271 ([M+H.H₂O]⁺) NI-MS m/z 287 ([M−H].), 269 ([M.H.H₂O]).

EXAMPLE 131 Norsanguinine (SPH-1486)

A solution of norgalanthamine (1.0 g, 3.66 mmol) in 40 ml of absoluteTHF is mixed at room temperature with 17 ml of L-selectride^(R) (1 M inTHF) and stirred for 24 hours at boiling temperature.

It is cooled to room temperature, mixed with ethyl acetate (20 ml), thenwith water (100 ml), and the phases are separated. The organic phase isextracted with water (4×20 ml), the combined aqueous phases areextracted with ethyl acetate (2×20 ml) and the residue that remainsafter concentration by evaporation is purified via column chromatography(100 g) of silica gel, chloroform:ammonia=90:9:1) and crystallized underacetone. In this way, the product is obtained in the form of colorlesscrystals (0.78 g, 82.3%).

¹H NMR (DMSO-d₆) δ 6.52-6.37 (m, 2H), 6.03 (d, J=10.3 Hz, 1H), 5.78 (dd,J=10.3 Hz, J=4.6 Hz, 1H), 4.43 (s, 1H), 4.09 (s, 1H), 3.90 (d, J=16 Hz,1H), 3.71 (d, J=16 Hz, 1H), 3.25-2.92 (m, 2H), 2.24-2.90 (m, 2H), 2.39(d, J=14 Hz, 2H)

¹³C NMR (DMSO-d₆): δ 145.6 (s), 140.4 (s), 133.0 (s), 132.3 (s), 127.7(d), 127.6 (d), 119.6 (d), 114.8 (d), 86.5 (d), 60.1 (d), 53.1 (t), 48.3(s), 46.6 (t), 40.2 (t), 30.8 (t)

EXAMPLE 132(4a,S,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol(SPH-1487)

(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-3-trifluoromethylsulfonyloxy-6H-benzofuro[3a,3,2-ef[2]benzazepin-6-ol(200 mg, 0.49 mmol), tetramethylstannane (106 mg, 0.59 mmol), anhydrouslithium chloride (62 mg, 1.47 mmol) and tetrakis triphenylphosphinepalladium (28 mg, 0.025 mmol, 0.05 equivalent) are stirred in absoluteDMF (3 ml) for 24 hours at 100° C. It is dispersed between water (20 ml)and ethyl acetate (30 ml), the aqueous phase is extracted with ethylacetate (5×30 ml), the combined organic phases are washed with water(3×10 ml) and saturated common salt solution (15 ml), and the residuethat is obtained after concentration by evaporation is purified bycolumn chromatography (20 g of silica gel, chloroform methanolammonia=96:3:1). In this way, the product is obtained in the form ofcolorless crystals (102 mg, 77%).

MT-298 JOS 1711

C₁₇H₂₁NO₂*0.25H₂O Cld.: C, 74.02; H, 7.86; N, 5.08 Fnd.: C, 73.77; H,7.67; N, 5.04

¹H NMR (CDCl₃): δ 6.90 (d, J=7.0 Hz, 1H), 6.46 (d, J=7.0 Hz, 1H), 6.08(d, J=11.5 Hz, 1H), 6.00 (dd, J=8.5 Hz, J=5.2 Hz, 1H), 4.54 (s, 1H),4.13 (s, 1H), 4.11 (d, J=16.5 Hz, 1H), 3.70 (d, J=16.5 Hz, 1H), 3.20 (t,J=12.7 Hz, 1H), 3.08 (d, J=12.7 Hz), 2.66 (dd, J=15.2 Hz, J=5.0 Hz, 1H),2.42 (s, 3H), 2.18 (s, 3H), 2.17-2.00 (m, 2H), 1.57 (dd, J=13.3 Hz,J=5.0 Hz, 1H);

¹³C NMR (CDCl₃): δ 156.4 (s), 135.3 (s), 131.6 (s), 130.1 (d), 127.7(d), 127.6 (d), 122.0 (d), 119.8 (s), 88.1 (d), 62.7 (d), 61.3 (t), 54.2(t), 48.5 (s), 42.4 (d), 33.9 (t), 30.4 (t), 15.3 (q).

EXAMPLE 136

SPH-1146 IK 66/1

(−) Cyclopropylmethylgalanthaminium bromide

Production analogously to Examples 90-99, melting point 230-237° C.

a^(D) ₂₀=−110 (C=1.5 in water)

EXAMPLE 137

SPH-1149 HM 104

(−) (3-Methylbut-2-en-1-yl)-galanthaminium bromide

Production analogously to Examples 90-99, melting point 198-201° C.

a^(D) ₂₀=−118.2 (1.5 in water)

EXAMPLE 138

SPH-1162 Cl 2-1 3au

3-((6R)-1-Bromo-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-11(12H)-yl)propanoicacid ethyl ester

Production analogously to Example 143

Reaction time: 8 hours, yield: 80% colorless foam

Same skeleton as in Example 143, here only the signals that aredifferent are indicated:

¹H NMR (CDCl₃) δ 4.13 (q, J=6.0 Hz, 2H), 2.85 (t, 7.0 Hz, 2H), 2.58 (t,J=7.0 Hz, 2H), 1.27 (t, J=6 Hz, 3H);

¹³C NMR (CDCl₃) δ 172.4 (s), 60.3 (t), 57.3 (t), 32.9 (t) 14.1 (q).

EXAMPLE 139

SPH-1184 LCz 225/1

(−) (4-Bromophenyl)methylgalanthaminium bromide hemihydrate

Production analogously to Examples go-99, Cld.: C 52.77, H 5.17, N 2.56Fnd.: C 52.45, H 5.15, N 2.52

EXAMPLE 140

SPH-1191 LCz 205

(−) (3-Chloropropyl)-galanthaminium bromide, 1.25 H₂O

Production analogously to Examples 90-99, Cld.: C 51.40, H 6.36, N 3.00Fnd.: C 51.08, H 6.07, N 2.92

EXAMPLE 141

SPH-1208 CB 2

(6R)-1-Bromo-6-hydroxy-N¹¹-isopropyl-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxylicacid amide

Production analogously to Example 142, yield: 96%;

¹H NMR (CDCl₃) δ 6.87 (s, 1H), 6.04 (dd, J=16.0; 10.0 Hz, 2H), 4.88 (d,J=18.0 Hz, 1H), 4.61 (m, 1H), 4.28 (d, J=18.0, 1H), 4.13 (b, 1H), 3.90(m, 1H), 3.85 (s, 3H), 3.26 (t, J=12.0 Hz, 1H), 2.67 (dd, J=16.0; 3.0Hz, 1H), 2.29 (d, J=10.0 Hz, 1H), 1.99 (m, 2H), 1.72 (d, J=17 Hz, 1H);1.12 (dd, J=20.0; 5.0 Hz, 6H); ¹³C NMR (CDCl₃) δ 156.0 (s), 146.5 (s),144.9 (s), 133.8 (s), 128.6 (d), 128.2 (s), 127.5 (s), 125.8 (d), 115.1(d) 112.3 (d), 88.5 (d), 61.6 (d), 56.1 (q), 50.3 (t), 49.1 (s), 45.2(t), 42.7 (d), 36.6 (t), 29.6 (t), 23.4 (q), 23.0 (q). Anal.[C₂₀H₂₅BrN₂O₄.0.3H₂O) Cld.: C 54.26 H 5.83 N 6.33 Fnd.: C 54.28 H 5.79 N6.14

EXAMPLE 142

SPH-1209 CB 5

(6R)-1-Bromo-6-hydroxy-3-methoxy-N11-methyl5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-thiocarboxylicacid amide

Methyl isothiocyanate (42.0 mg, 0.57 mmol) was added in drops to astirred solution of bromonorgalanthamine (0.2 g, 0.57 mmol) in toluene(10 ml), and it was refluxed for three hours. After concentration byevaporation, the residue was taken up in 2N HCl (20 ml) and washed withAcOEt (1×10 ml). The aqueous solution was brought to a pH>8.5 withconcentrated ammonia and extracted with AcOEt (3×10 ml). The combinedorganic phases were washed with saturated common salt solution, dried(Na₂SO₄) and concentrated by evaporation, by which the product wasobtained in the form of colorless crystals with a melting point of183-185° C. (0.22 g, 99%);

¹H NMR (CDCl₃) δ 7.35 (b, 1H), 6.89 (m, 1H), 6.10 (m, 2H), 5.50 (d,J=12.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 4.69 (b, 1H), 4.52 (d, J=12.0Hz, 1H), 4.17 (b, 1H), 3.85 (s, 3H), 3.60 (t, J=18.0 Hz, H), 3.10 (d,J=3.4 Hz, 3H), 2.72 (dd, J=18.8; 2.0 Hz, 1H), 2.13 (m, 2H), 1.79 (d,J=12.0 Hz, 1H); ¹³C-NMR (CDCl₃) δ 181.5 (s), 146.8 (s), 145.4 (s), 133.9(s), 128.9 (d), 128.2 (s), 125.5 (d), 115.3 (d), 112.5 (d), 88.6 (d),61.5 (d), 56.2 (q), 51.7 (t), 51.2 (t), 48.9 (s), 35.8 (t), 33.0 (q),29.6 (t).

Anal. (C₁₈H₂₁BrN₂O₃S.0.5 H₂O) Cld.: C 50.83 H 4.98 N 6.59 Fnd.: C 50.73H 5.02 N 6.63

EXAMPLE 143

SPH-1210 CB 4

3-((6R)-1-Bromo-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[I]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)propanenitrile

Acrylonitrile (0.05 ml, 0.85 mmol) and calcium chloride (200 mg, 1.80mmol) were added to a solution of norgalanthamine (200 mg, 0.57 mmol) in50% EtOH (20 ml), and the reaction was refluxed for 3 hours. Thereaction was concentrated, the residue was taken up in 2N.HCl (50 ml)and washed with EtOAc (3×25 ml, the organic phase was discarded). Theaqueous solution was brought to pH>8.5 with concentrated NH₃ andextracted with methylene chloride (3×25 ml). The combined organic phaseswere washed with saturated sodium chloride solution (200 ml), dried(Na₂SO₄) and concentrated by evaporation, and the product, 220 mg(95.7%), was obtained as a colorless foam.

¹H NMR (CDCl₃) δ 6.90 (s, 1H), 6.04 (dd, J₁=16.0 Hz, J₂=10.0 Hz, 2H),4.60 (b, 1H), 4.38 (d, J=16.0, 1H), 4.12 (b, 1H), 4.08 (d, J=16.0 Hz,1H), 3.83 (s, 3H), 3.47 (t, J=10.0 Hz, 1H), 3.18 (d, J=18.0 Hz, 1H),2.80 (t, J=10.0 Hz, 2H), 2.63 (m, 2H), 2.61 (m, 1H), 2.03 (m, 2H), 1.60(d, J=10.0 Hz, 1H); ¹³C-NMR (CDCl₃) δ 145.6 (s), 144.5 (s), 134.1 (s),128.4 (d), 127.1 (s), 126.1 (d), 118.6 (s), 115.8 (d), 114.3 (d), 88.7(d), 61.7 (d), 56.1 (q), 54.9 (t), 52.0 (t), 48.9 (s), 47.2 (t), 33.3(t), 29.7 (t), 16.8 (t)

Anal. (C₁₉H₂₁BrN₂O₃) Cld.: C 56.31 H 5.22 N 6.91 Fnd.: C 56.53 H 5.44 N6.64

EXAMPLE 144

SPH-1227

[4aS-(4aα,6α,8aR*)]-4a,5,9,10,11,12-Hexahydro-3-methoxy-11-ethyl-6H-benzofuro[3a,3,2-ef][2]benzazepine-6-amineStep 1

A solution of 300 mg (1.05 mmol) of galanthamine, 208 mg (1.20 mmol) ofazadicarboxylic acid diethyl ester, 314 mg (1.20 mmol) oftriphenylphosphine and 1.20 mmol of phthalimide in 30 ml of absolutetetrahydrofuran is stirred for 24 hours at room temperature. Then, thetetrahydrofuran is spun off, the residue is taken up in 30 ml of 2Nhydrochloric acid, washed three times with 30 ml each of ethyl acetateand made basic with concentrated aqueous ammonia. Then, the solution isextracted three times with 30 ml each of ethyl acetate, the combinedorganic phases are washed once with saturated aqueous sodium chloridesolution, dried (Na₂SO₄), filtered and concentrated by evaporation. Thecrude product is purified by FLC (15 g of silica gel, mobile solvent:CHCl₃:MeOH=97:3).

83% colorless crystals, melting point: 60-63° C.

TLC: CHCl₃:MeOH=9:1

Step 2

146 mg (1.44 mmol) of triethylamine and 162 mg (1.58 mmol) of3-(dimethylamino)propylamine are added in drops to a solution, cooled to—5° C., of 0.72 mmol of educt in 5 ml of absolute methanol. Then, thereaction mixture is allowed to stir at room temperature for 24 hours,and then methanol, triethylamine and 3-(dimethylamino)propylamine arespun off. The crude product that is obtained is purified by FLC (15 g ofsilica gel, mobile solvent: CHCl₃:MeOH=9:1 with 0.5% concentratedaqueous ammonia), by which colorless crystals with a melting point of119-121° C. with a rotation of α_(D) ²⁰ [c=0.1, CHCl₃]=−264° of productare obtained.

TLC: CHCl₃:MeOH=9:1

¹H NMR (CDCl₃): δ 1.56-1.89, m, 2H, 2.78, m, 1H; 3.02, m, 1H; 3.24, m,1H; 3.48, m, 1H; 2.32, s, 1H; 3.83, s, 1H; 3.63, d, 1H; 4.07, d, 1H;4.62, b, 1H; 4.98, b, 1H; 5.74, d, 1H; 6.11, d, 1H; 6.54, d, 1H; 6.64,d, 1H.

EXAMPLE 145

SPH-1273 CB 99

(4aS,6R,8aS)-11-Methyl-3-phenoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef](2]benzazepin-6-ol

0.44 g (3.6 mmol) of benzeneboric acid, 2.5 ml (9 mmol) oftriethylamine, 0.67 g (3.6 mmol) of copper(II) acetate and 1 g ofmolecular sieve (4 Å, crushed) were added to a solution of 1.0 g (3.6mmol) of O-demethylgalanthamine in 50 ml of dichloromethane. Thereaction mixture was stirred for 44 hours at room temperature. The solidwas filtered off. The filtrate was extracted twice with 30 ml each ofsaturated sodium bicarbonate solution. The aqueous phase wasre-extracted three times with 30 ml of methylene chloride in each case.The combined organic phases were dried on sodium sulfate, and thesolvent was distilled off. The crude product (0.55 g, 43.7% of theory)was purified by means of column chromatography (CHCl₃:MeOH=95:5).

Yield: 0.3 g (23.8% of theory)

TLC: CHCL₃: CH₃OH=9:1

CB 99:

¹H NMR (CDCl₃): δ 7.29 (m, 2H), 7.04 (t, J=7.2 Hz, 1H), 6.89 (d, J=8.7Hz, 2H), 6.73 (dd, J₁=31.6 Hz, J₂=8.7 Hz, 2H), 6.03 (m, 2H), 4.59 (s,1H), 4.51 (b, 1H), 4.17 (d, J=15.3 Hz, 1H), 3.77 (d, J=15.3 Hz, 1H),3.33 (t, J=13.0 Hz, 1H), 3.10 (d, J=14.5 Hz, 1H), 2.53 (m, 1H), 2.43 (s,3H), 2.15 (m, 1H), 1.89 (m, 1H), 1.62 (d, J=13.8, 1H); ¹³C-NMR (CDCl₃):δ 157.3 (s), 148.1 (s), 139.6 (s), 134.2 (s), 129.6 (2*d), 128.1 (d),126.2 (d), 122.8 (d), 122.7 (d), 120.2 (d), 116.8 (d), 88.7 (d), 61.7(d), 59.9 (t), 53.2 (t), 48.1 (s), 41.2 (q), 32.8 (t) 29.7 (t).

Anal. (C₂₂H₂₃NO₃*0.2 CHCl₃) Cld.: C 71.43 H 6.26 N 3.75 Fnd.: C 71.43 H6.61 N 3.84

EXAMPLE 146

SPH-1288 HM 122.DD 13

(6R)-3,6-Dihydroxy-N¹¹-isopropyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxylicacid amide

A solution of 0.42 ml (4.3 mmol) of boron tribromide in 4 ml of absolutedichloromethane was slowly added in drops under argon at −5° C. to asolution of 1.6 mmol of educt in 17 ml of absolute dichloromethane.After 3 hours of stirring at −5 to 0° C., the reaction mixture waspoured onto 20 ml of water and saturated with sodium bicarbonate. Theaqueous phase was extracted four times with 15 ml each of n-butanol, andthe solvent was distilled off. The residue was purified by means ofcolumn chromatography (LM: CHCl₃ CH₃OH=97:3) and dried at 50° C./50mbar.

¹H NMR (CDCl₃) δ 6.57 (dd, J₁=18.7 Hz, J₂=8.0 Hz, 2H), 5.94 (dd, J₁=21.4Hz, J₂=10.4 Hz, 2H), 4.90 (dd, J₁=10.6 Hz, J₂=6.0 Hz, 1H), 4.36 (m, 3H),3.85 (m, 1H), 3.33 (t, J=12.1 Hz, 1H), 2.93 (m, 1H), 2.25 (m, 1H), 1.87(m, 2H), 1.24 (m, 1H), 1.06 (dd, J₂=21.3 Hz, J₂=6.5 Hz, 6H); ¹³C-NMR(CDCl₃): δ 156.7 (s), 146.5 (s), 141.0 (s), 131.5 (s), 130.1 (s), 128.1(d), 127.1 (d), 120.1 (d), 115.5 (d), 88.2 (d), 51.6 (t), 48.0 (s), 45.9(t), 42.8 (d), 42.0 (d), 36.8 (t), 34.2 (t), 23.5 (q), 23.1 (q)

Anal. (C₁₉H₂₄N₂O₄*0.8 CHCl₃) (JOS 1622). Cld.: C 54.0 H 5.68 N 6.37Fnd.: C 54.08 H 5.61 N 6.33

EXAMPLE 147

SPH-1302 HM 203

(4aa,6β,8aR*)-4a,5,9,10-Tetrahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-carboxylicacid-1,1-dimethylethyl ester (8d)

A solution of 9.00 g (41.30 mmol) of pyrocarbonic acid-di-tert-butylester in 150 ml of absolute tetrahydrofuran was added in drops whilebeing cooled with ice to a solution of 12.0 g of a mixture ofnorgalanthamine and galanthamine at a ratio of 94:6 (corresponding to41.3 mmol of norgalanthamine) and 7.10 g (70.2 mmol) of triethylamine in400 ml of absolute tetrahydrofuran. After 10 minutes, the ice-coolingwas removed, and it was stirred for 16 hours at room temperature. Then,the organic solvent was evaporated, the residue was taken up in ethylacetate, and it was washed three times with 150 ml each of 1N aqueoushydrochloric acid, three times with 200 ml each of saturated sodiumbicarbonate solution and twice with 200 ml each of saturated sodiumchloride solution. The solvent was dried on sodium sulfate, concentratedby evaporation, and the crude product was purified by means of MPLC:mobile solvent: chloroform:methanol 99:1→90:10. 11.2 g of white foam wasobtained at HM 203 (73% of theory).

TLC: CHCl₃:MeOH/NH₃ 9:1

¹H-NMR (CDCl₃, 200 MHz): 1.35-1.45 (m, 9H), 1.75 (m, 1H), 1.97 (m, 1H),2.05 (m, 1H), 2.40 (m, 1H), 2.69 (b, 1H), 3.30 (b, 1H), 3.85 (OCH₃, s,3H), 4.08-4.17 (m, 3H), 4.60 (b, 1H), 5.97-6.06 (m, 2H), 6.70-6.78 (m,2H)

Anal. (C₂H₂₇NO₅, 0.4 MeOH) Cld.: C 66.54 H 7.46 N 3.63 Fnd.: C 66.59 H7.59 N 3.47

EXAMPLE 149

SPH-1339 HM 264-1

(4aS,6R,8aS)-11-Propyl-3-methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol

Method 1:

A solution of 250 mg (0.92 mmol) of (−)-norgalanthamine and 160 mg (2.76mmol) of propanal in 20 ml of absolute acetonitrile were mixed inportions with 145 mg (2.3 mmol) of sodium cyanoborohydride and stirredfor 12 hours at room temperature. Then, 145 mg (2.3 mmol) of sodiumcyanoborohydride was repeatedly added in portions, and the reactionmixture was stirred for another 6 hours. After the solvent wasevaporated, the working-up was carried out according to instructions A1.Further purification was carried out by means of MPLC (mobile solvent:chloroform:methanol/NH₃=95:5). 200 mg (70% of theory) of HM 264 wasobtained.

TLC: CHCl₃:MeOH/NH₃ 9:1

Method 2:

A solution of 200 mg (0.73 mmol) of (−) norgalanthamine and 120 mg (1.46mmol) of sodium acetate in 12 ml of water, 4 ml of absolute ethanol and0.62 ml of glacial acetic acid was cooled to 0° C., mixed with 211 mg(3.65 mmol) of propanal and stirred for 5 minutes. Then, 138 mg (3.65mmol of sodium borohydride in 10 mg portions was added. After 20minutes, another 211 mg (3.65 mmol) of propanal and 138 mg (3.65 mmol)of sodium borohydride were added and stirred for 30 minutes. Then, thereaction mixture was worked up as described in Instructions A1. 210 mg(91% of theory) of HM 264 was obtained.

TLC: CHCl₃:MeOH/NH₃ 9:1

¹H-NMR (CDCl₃, 200.13 MHz): δ 0.88 (t, J=7.2, 3H), 1.96-2.11 (m, 2H),2.45 (sextet, J=7.8, J=4.6, J=5.0 Hz, 2H), 2.68 (ddd, J=15.7, J=1.8,J=1.8, 1H), 3.18 (ddd, J=14.9, J=3.1, J=3.1 Hz, 1H), 3.35 (ddd, J=14.4,J=2.2, J=1.9, 1H), 3.80 (d, J=15.3 Hz, 1H), 3.85 (s, 3H), 4.10 (d,J=15.3, 1H), 4.12 (b, 1H), 4.60 (b, 1H), 5.96-6.13 (m, 2H), 6.61 (d,J=8.2, 1H), 6.68 (d, J=8.2, 1H); ¹³C-NMR (CDCl₃, 50.32 MHz): δ 11.8 (q),20.5 (t), 29.9 (t), 32.9 (t), 48.4 (s), 51.4 (t), 53.5 (t), 55.8 (q),57.7 (t), 62.0 (d), 88.6 (d), 111.1 (d), 121.9 (d), 127.0 (d), 127.4(d), 129.6 (s), 133.1 (s), 143.9 (s), 145.7 (s)

EXAMPLE 150

SPH-1340 HM 265-1

N-Demethyl-N-propargyl-galanthamine

A solution that consists of 0.50 g (1.83 mmol) of(−)demethylgalanthamine, 0.51 g (3.66 mmol) of potassium carbonate and0.55 g (3.66 mmol) of sodium iodide in 25 ml of is dimethylformamide wasmixed with 2.20 mmol of reagent and heated for six hours to 70-80° C.Then, the solvent was evaporated. The residue was taken up in 50-100 mlof 2N aqueous hydrochloric acid and washed twice with 40-70 ml each ofethyl acetate. Then, it was made basic with concentrated aqueous ammoniaand extracted three times with 40-70 ml each of dichloromethane. Thecombined organic phases were washed twice with 40-70 ml each ofsaturated sodium chloride solution, dried on sodium sulfate, and thesolvent was evaporated.

The further purification was carried out by means of MPLC (mobilesolvent: chloroform:methanol/NH₃=95:5).

Yield: 0.26 g (46% of theory) of a colorless oil

TLC: CHCl₃:MeOH/NH₃9:1

¹H-NMR (CDCl₃, 200.13 MHz): δ 1.53 (ddd, J=13.8, J=3.7, =2.1, 1H),1.89-2.09 (m, 4H), 2.27 (t, J=2.3, 2H), 2.65 (ddd, J=15.8, J=1.6, J=1.6,1H), 3.15-3.43 (m, 2H), 3.79 (d, J=15.0 Hz, 1H), 3.85 (s, 3H), 4.11 (d,J=15.0 Hz, 1H), 4.13 (b, 1H), 4.58 (b, 1H), 5.91-6.09 (m, 2H), 6.63 (b,2H) ¹³C-NMR (CDCl₃, 50.32 MHz): δ 29.9 (t), 34.5 (t), 44.2 (t), 48.0(s), 51.5 (t), 55.8 (q), 58.2 (t), 61.9 (d), 72.8 (s), 79.4 (d), 88.6(d), 111.3 (d), 122.0 (d), 126.8 (d), 127.6 (d), 128.7 (s), 132.9 (s),144.1 (s), 145.8 (s)

EXAMPLE 151

SPH-1357 MF 8

Production analogously to Example 6/step 3, but with use of2-(4-bromobutyl)-5-methoxyindan-1-one, colorless foam.

¹H-NMR (ppm, CDCl₃): δ 7.65 (d, J=8.1 Hz, 1H), 6.87 (d, J=7.7 Hz, 2H),6.62 (dd, J₁=12.9 Hz, J₂=8.4 Hz, 2H), 6.04 (m, 2H), 4.60 (b, 1H), 4.14(m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.81 (m, 1H), 3.61 (d, J=6.24 Hz,1H), 3.25 (m, 2H), 2.88 (d, J=15.1, 5H), 2.52 (b, 1H), 2.07 (m, 3H),1.93 (m, 1H), 1.64-1.48 (m, 4H);

¹³C-NMR (ppm, CDCl₃) 207.0 (s), 165.3 (s), 162.5 (s), 156.6 (s), 145.8(s), 144.1 (s), 133.1 (s), 129.5 (s), 127.6 (d), 126.9 (d), 122.0 (d),115.2 (d), 111.2 (d), 109.6 (d), 88.7 (d), 62.0 (t), 57.6 (t), 55.9 (q),55.8 (q), 51.5 (t), 48.4 (d), 47.6 (d), 32.8 (t), 31.5 (t), 29.9 (t),29.6 (t), 27.4 (t), 25.1 (t).

EXAMPLE 155

SPH-1377 BK-34-2

2-[4-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]butyl]-5-methoxyindan-1-one,fumarate

Production of Example 151 analogously to Example 7/production offumarate.

Melting point: 107-110° C.

C₃₀H₃₅NO₅ 5/4C₄H₄O₄ 1H₂O Cld.: C, 64.07 H, 6.44 N, 2.11 Fnd.: C, 64.26H, 6.41 N, 2.23

¹H NMR (ppm, CDCl₃): δ 7.56 (d, J=10 Hz, 1H), 7.10 (s, 1H), 6.98 (d,J=10 Hz, 1H), 6.80 (m, 2H), 6.63 (s, 2H), 6.13 (d, J=12.0 Hz, 1H), 5.89(m, 1H), 4.61 (s, 1H), 4.50 (d, J=8.0 Hz, 1H), 4.07 (b, 2H), 3.88 (s,3H), 3.72 (s, 3H), 3.52 (t, J=12 Hz, 1H), 3.31 (m, 2H), 2.69 (m, 5H),2.30 (d, J=12 Hz, 1H), 2.07 (m, 2H), 1.74 (m, 4H), 1.38 (m, 3H); ¹³C-NMR(ppm, CDCl₃) 206.3 (s), 166.9 (s), 165.3 (s), 157.2 (s), 146.3 (s),144.6 (s), 133.1 (d), 129.7 (s), 129.4 (s), 126.4 (d), 125.1 (d), 122.5(d), 115.8 (d), 112.7 (d), 110.3 (d), 86.8 (d), 65.3 (t), 60.0 (t), 56.1(q), 55.8 (q), 51.1 (t), 47.5 (d), 46.9 (d), 32.5 (t), 32.5 (t), 31.9(t), 31.2 (t), 30.8 (t), 24.9 (t), 24.2 (t).

EXAMPLE 157

SPH-1515

(4aS,6R,8aS)-3,6-Dihydroxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylicacid allyl ester (ML-7)

2.11 ml (1.538 g, 19.3 mmol) of triethylamine and 0.81 ml (0.693 g,6.384 mmol) of trimethylsilyl chloride are sprayed under inert-gasatmosphere by means of a syringe through a septum into a suspension of0.788 g (0.552 g, 2.13 mmol) of norsanguinine (HPLC purity 70%) and 10ml of absolute dichloromethane, and the suspension is stirred for threehours at room temperature. In the meantime, a flocculent precipitatesettles out. Then, 0.34 ml (0.385 g, 3.192 mmol) of allyl chloroformateis added while being cooled in an ice bath (exothermic). The reactionmixture is heated within two hours to room temperature while beingstirred, by the ice bath being allowed to thaw. The reaction is haltedby adding 13 ml of 2N hydrochloric acid, and the phases are separated.The organic phase is washed four times with 10 ml each of 2Nhydrochloric acid and once with common salt solution, the combinedaqueous phases are re-extracted once with 20 ml of dichloromethane. Thecombined organic phases are dried on sodium sulfate and filtered. Afterthe solvent is distilled off in a rotary evaporator, the crude product(HPLC purity 87.5%) is purified by means of MPLC (50 g of silica gel,v=285 nm, chloroform/methanol=95/5). After concentration by evaporationand drying in a high vacuum, the product is obtained as a yellowish,highly viscous oil, which crystallizes during concentration byevaporation from dichloromethane. Yield: 0.443 g (1.29 mmol, 61%) ofcolorless crystalline solid, (M_(w)=343.4), TLC: R_(f)=0.55(chloroform/methanol=9/1).

Melting point: 197-198° C. (dichloromethane)

¹H-NMR: (200.13 MHz, CDCl₃, TMS) δ 7.66 (bs, 0.3H), 6.52-6.76 (m, 2H),5.95 (bs, 2H), 5.72-5.90 (m, 1H), 5.06-5.36 (m, 2H), 4.90 (d, J=12.7 Hz,0.5H), and 4.79 (d, J=12.7 Hz, 0.5H), 4.51 (bs, 3H), 4.00-4.41 (m, 3H),3.22-3.53 (m, 1H), 3.13 (bs, 0.3H), 2.58 (bd, J=13.4 Hz, 1H), 1.63-2.10(m, 3H), ¹³C-NMR: (50.32 MHz, CDCl₃, TMS), δ 155.4 and 155.2 (s), 145.4(s), 140.6 (s), 132.7 and 132.6 (d), 131.9 and 131.7 (s), 128.3 (s),127.1 (d), 127.0 (d), 121.6 and 121.1 (d), 117.4 and 116.8 (t), 115.8and 115.7 (d), 87.7 (d), 66.1 and 65.9 (t), 61.8 (d), 51.9 and 51.5 (t),48.4 (s), 45.9 and 45.4 (t), 37.0 and 36.0 (t), 29.5 (t).

EXAMPLE 158

SPH-1522

4aS,6R,8aS)—N¹¹-(N-tert-Butoxycarbonyl-6-aminohexyl)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro-[3a,3,2-ef]-[2]benzazepine-11(12H)carboxamide (CK-52-6)

0.600 g (0.426 mmol) ofN-tert-butoxycarbonylnorgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifieldresin is steeped in a 10-ml-polyethylene frit that can be sealed on bothsides for 30 minutes in a sufficient amount of dichloromethane anddemasked analogously to the protection removal instructions toimmobilize N-tert-butoxycarbonylnorgalanthamine (Example 147) and washed(in each case 6 ml of solvent). Then, the resin is reacted analogouslyto the above instructions with 730 μl (0.551 g, 4.260 mmol) ofethyldiisopropylamine and 0.379 g (1.278 mmol) of triphosgene in 6 ml ofabsolute dichloromethane. After the resin is washed and dried in avacuum overnight, 0.653 g ofN-chclorocarbonylnorgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifieldresin is obtained.

After the resin (0.103 g, 0.065 mmol) is steeped and filtered, it issuspended in a solution that consists of 0.164 g (0.650 mmol) ofN-tert-butoxycarbonyl-1,6-diaminohexanehydrochloride, 222 μl (0.168 g,1.300 mmol) of ethyldiisopropylamine, 0.053 μl (0.051 g, 0.650 mmol) ofpyridine and 2.0 ml of dimethylformamide (to dissolve the hydrochloride,the solution is heated beforehand). Then, the suspension is shaken atroom temperature for 5.5 hours. The resin is washed three times withdimethylformamide (2 minutes, 1 ml) and six times with dichloromethane(2 minutes, 1 ml). After drying in a vacuum, the resin is shaken in 2 mlof tetrahydrofuran for 30 minutes, and after filtering, it is mixed witha solution that consists of 0.059 g (0.018 g, 0.325 mmol), 30% of sodiummethanolate-methanol solution and 1.5 ml of tetrahydrofuran/methanol(4/1). After 9.5 hours of shaking at room temperature, the solution isfiltered off, and the resin is extracted three times with 1.5 ml each ofdichloromethane/methanol (1/1) and three times with 1.5 ml each ofdichloromethane. The combined filtrates are neutralized with methanolichydrochloric acid, diluted with 10 ml of dichloromethane, washed oncewith 15 ml of 2N hydrochloric acid and twice with 15 ml each ofsaturated sodium chloride solution, dried on sodium sulfate, filteredand concentrated by evaporation under reduced pressure in a rotaryevaporator. The crude product (0.051 g) is separated by means of columnchromatography (5 g of silica gel, chloroform/methanol=50/1).

After concentration by evaporation, a colorless oil is obtained.

Yield: 0.030 g (0.058 mmol, 89%), colorless oil (M_(w)=515.7)

TLC: R_(f)=0.47 (chloroform/methanol=9/1)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

6.73 (d, J=8.1 Hz, 1H), 6.66 (d, J=8.3 Hz, 1H), 5.90-6.07 (m, 2H),4.23-4.70 (m, 5H), 4.13 (bs, 1H), 3.82 (s, 3H), 3.35 (t, J=13.5 Hz,1.0H), 2.96-3.20 (m, 4H), 2.67 (bd, J=15.7 Hz, 1H); 1.65-2.10 (m, 3H),1.42 (s, 9H), 1.06-1.40 (m, 8H)

¹³C NMR: (50.32 MHz, CDCl₃, TMS)

δ 157.2, 156.0, 147.0, 144.7, 132.5, 129.2, 128.1, 126.5, 120.2, 111.2,88.4, 61.9, 55.9, 51.7, 48.5, 45.7, 42.1, 40.5, 39.3, 36.6, 30.0, 29.7,28.4, 26.1, 23.5

HPLC: t_(Ref)=17.8 minutes, 98.7% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5.0 μm, 1 ml/minute, 285 nm, acetonitrile/20 mmol ofCl₃CCO₂H in H₂O (20/80 for 5 minutes, 20/80→60/40 in 12 minutes, 60/40for 5 minutes, v/v)

EXAMPLE 159N-tert-Butyloxycarbonylglycine-[4-[(4aS,6R,8aS)-6-hydroxy-3-ethoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl]-3-aza-4-oxobutyl]amide(CK-58-2)

0.199 g (0.102 mmol) ofnorgalanathamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifield resin issteeped in a 5-ml-polyethylene frit that can be sealed on both sides for30 minutes in 2 ml of dichloromethane, and after filtering, it issuspended in a solution of 120 μl (0.091 g, 0.700 mmol) ofethyldiisopropylamine in 1.5 ml of dichloromethane. Then, the suspensionis mixed with a solution, cooled to 0° C., that consists of 0.062 g(0.210 mmol) of triphosgene and 0.5 ml of dichloromethane and shaken atroom temperature for two hours. The resin is washed three times withdichloromethane (2 minutes, 2 ml) and three times with dimethylformamide(2 minutes, 2 ml). A solution that consists of 47 μl (0.042 g, 0.700mmol) of ethylenediamine and 2.0 ml of dimethylformamide is subsequentlyadded, and the suspension is shaken at room temperature. After threehours, the solution is filtered off, and the resin is washed six timeswith 2 ml each of dimethylformamide (2 minutes). (The Kaiser Test cannotbe evaluated. The beads exhibit brown-red staining.) The resin is mixedwith a solution that consists of 0.037 g (0.210 mmol) of N—BOC-glycine,0.028 g (0.210 mmol) of 1-hydroxybenzotriazole and 1 ml ofdimethylformamide, and the suspension is shaken for five minutes. Then,0.043 g (0.210 mmol) of dicyclohexylcarbodiimide, dissolved in 1 ml ofdichloromethane, is added. The suspension is shaken for three hours atroom temperature, the resin is filtered, and it is washed three timeswith dimethylformamide (2 ml, 2 minutes) and six times withdichloromethane (2 ml, 2 minutes). After drying in a vacuum, 0.239 g ofresin, which is shaken in tetrahydrofuran for 30 minutes, is obtained,and after filtering, it is mixed with a solution that consists of 0.076g (0.023 g, 0.63 mmol) of 30% sodium methanolate-methanol solution and2.0 ml of tetrahydrofuran/methanol (4/1). After 8.25 hours of shaking,the solution is filtered off, and the resin is extracted three timeswith 2 ml each of dichloromethane/methanol (1/1) and three times with 2ml each of dichloromethane. The combined filtrates are neutralized withmethanolic hydrochloric acid, diluted with 10 ml of dichloromethane,washed twice with 15 ml of saturated sodium chloride solution, dried onsodium sulfate, filtered and concentrated by evaporation in a rotaryevaporator under reduced pressure. The crude product (0.064 g) isseparated by means of column chromatography (5 g of silica gel,chloroform/methanol=25/1 15/1). After the concentration by evaporation,a colorless oil is obtained.

Yield: 0.030 g (0.025 g, 0.048 mmol, 47%), colorless oil (M_(w)=516.6)

TLC: R_(f)=0.38 (chloroform/methanol=9/1)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 6.90 (bs, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.60-6.71 (m, 1H), 5.88-6.08(m, 2H), 5.39 (bs, 1H), 5.19 (bs, 1H), 4.50-4.70 (m, 2H), 4.04-4.34 (m,3H), 3.82 (s, 3H), 3.70 (d, J=6.1 Hz, 1H), 3.65 (d, J=5.6 Hz, 1H),3.11-3.49 (m, 5H), 2.68 (d, J=15.9 Hz, 1H), 2.41 (d, J=10.9 Hz, 1H),1.65-2.09 (m, 3H), 1.44 (s, 9H)

HPLC: t_(Ref)=15.2 minutes, 82.3% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5.0 μm, 1 ml/minute, 285 nm, MeOH/H₂O (5/95 for 5 minutes,5/95→100/0 in 15 minutes (convex), 100/0 for 10 minutes, v/v)

LC/MS: t_(Ref)=30.6 minutes, (Phenomenex Luna column, 3.0 mm×50 mm,RP-18, 3.0 μm, 0.8 ml/minute,

methanol/H₂O (10/90 for 2 minutes, 10/90 100/0 in 15 minutes, 100/0 for5 minutes, vv)

APCI-PI-MS

517 (17), 499 (5), 461 (55), 443 (39), 417 (100), 399 (18), 274 (43),256 (16)

EXAMPLE 160

SPH-1524

(4aS,6R,8aS)-6-(Benzoyloxy)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylicacid allyl ester (CK-65-1)

0.075 g (0.210 mmol) of N-allyloxycarbonylnorgalanthamine, 0.475 g(2.098 mmol) of benzoic acid anhydride and 0.013 g (0.105 mmol) ofdimethylaminopyridine are introduced into 2 ml of dichloromethane andthen mixed with 0.185 ml (0.136 g, 1.049 mmol) of ethyldiisopropylamine.After 13 hours at room temperature, the solution is taken up with 5 mlof saturated sodium bicarbonate solution, and extracted three times with5 ml each of ethyl acetate. The combined organic extracts are washedwith 10 ml of saturated sodium bicarbonate solution, twice with 10 ml of2N hydrochloric acid and twice with 10 ml of saturated sodium chloridesolution, dried on sodium sulfate, filtered and concentrated byevaporation in a rotary evaporator under reduced pressure. The residueis digested twice in each case with 10 ml of petroleum ether, and thesolution is decanted off. The residue (0.100 g) is purified by columnchromatography (10 g of silica gel, mobile solvent=petroleum ether/ethylacetate=2/1).

Yield: 0.066 g (0.080 mmol, 68%), colorless foam (M_(w)=461.5)

TLC: R_(f)=0.52 (ethyl acetate/petroleum ether=2/1)

Melting point: 45-49° C. (ethyl acetate/petroleum ether=2/1)

IR: KBr

v (cm⁻¹) 2946 (m), 1708 (s), 1509 (m), 1483 (m), 1276 (s), 1108 (m),1056 (m), 714 (m)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 8.06 (d, J=7.1 Hz, 1H), 7.29-7.61 (m, 3H), 6.59-6.84 (m, 2H), 6.28 (d,J=10.3 Hz, 5H), 6.07 (dd, J=5.0 Hz, J=10.2 Hz, 1H), 5.76-5.99 (m, 1H),5.59 (t, J=4.4 Hz, 1H), 5.09-5.35 (m, 2H), 4.87 (dd, J=15.7 Hz, J=22.0Hz, 1H), 4.05-4.70 (m, 5H), 3.89 (s, 3H), 3.29-3.60 (m, 1H), 2.81 (bd,J=16.1 Hz, 1H), 1.74-2.25 (m, 3H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 166.2 (s), 155.3 and 155.1 (s), 147.4 and 147.3 (s), 144.3 (s), 132.99and 132.85 (d), 131.7 (d), 131.4 and 131.0 (s), 130.4 (s), 129.9 (d),128.4 (d), 127.1 (d), 120.7 and 120.2 (d), 117.4 and 116.8 (t), 111.4and 111.3 (d), 86 (d), 66.1 and 66.0 (t), 63.4 (d), 56.0 (q), 63.8 (d),S1.9 and 51.4 (t), 48.3 (s), 45.8 and 45.4 (t), 37.9 and 37.0 (t), 27.8(t)

EXAMPLE 161

SPH-1525

Immobilization of(4aS,6R,8aS)-3,6-Dihydroxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef]-[2]benzazepine-11(12H)-yl)carboxylicacid allyl ester on a para-hydroxymethylphenoxy-polystyrene resin (Wangresin)

Method A (CK-63-2)

0.257 g (0.244 mmol) of Wang resin² is stirred under argon atmosphere in3 ml of absolute dichlororomethane for 15 minutes. Then, 86 μl (0.141 g,1.19 mmol) of thionyl chloride is added in drops within five minutes at0° C. The suspension is stirred at 0° C. for one hour. Then, the resinis moved to a polyethylene frit that can be sealed on both sides, and itis washed five times with dichloromethane (2 minutes, 2.5 ml), twicewith methanol (2 minutes, 2.5 ml), once with dichloromethane (2 minutes,2.5 ml) and once with diethyl ether (2 minutes, 2.5 ml). The resin isthen dried in a vacuum on phosphorus pentoxide.²P-Alkoxybenzyl alcohol resin, D-1250, Bachem Feinchemikalien AG

Step 1

0.2334 g of the chlorine-Wang resin that is thus produced, 0.232 g(0.713 mmol) of cesium carbonate, 0.088 g (0.238 mmol) oftetra-n-butylammonium iodide and 0.245 g (0.713 mmol) ofN-alloc-norsanguinine are suspended in 3 ml of absolutedimethylformamide while being stirred. Then, the suspension is stirredfor 24 hours at 60° C. After five hours, 1 ml of dimethylformamide isadded to suspend the deposited precipitate. Then, the resin is moved toa polyethylene frit that can be sealed on both sides withdimethylformamide/water solution (2/1), and it is washed twice withdimethylformamide/water solution (2/1, 2 minutes, 2.5 ml), twice withdimethylformamide/water-solution (1/2, 2 minutes, 2.5 ml), twice withmethanol/water solution (1/1, 2 minutes, 2.5 ml), twice with methanol (2minutes, 2.5 ml) and six times with dichloromethane (2 minutes, 2.5 ml).

Method B (CK-63-1)

0.121 ml (0.192 g, 1.247 mmol) of carbon tetrachloride is introducedinto 2.0 ml of absolute dichloromethane at 0° C. While being stirred(KPG-stirrer), 0.311 g (1.188 mmol) of triphenylphosphine, dissolved in1.0 ml of absolute dichloromethane, is added in drops within 15 minutesat 0° C. It is stirred for another ten minutes at 0° C. and then foranother ten hours at room temperature, until triphenylphosphine can nolonger be detected by thin-layer chromatography. 0.2506 g (0.238 mmol)of Wang resin¹ and 1.5 ml of dichloromethane are subsequently added, andthe suspension is stirred for 35 hours at room temperature (300 s⁻¹).The working-up of the chlorinated Wang resin is carried out analogouslyto method A. After drying, 0.2403 g of chlorine-Wang resin, which isreacted analogously to step 1 above with the same amounts of cesiumcarbonate, tetra-n-butylammonium iodide and N-alloc-norsanguinine, isobtained.

EXAMPLE 162

SPH-1526

Determination of Concentration,(4aS,6R,8aS)-6-(Benzoyloxy)-3-hydroxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylicacid allyl ester 1.1.1 Step 1 (CK-63-2)

To determine the concentration and to detect that theN-alloc-norsanguinine is bonded via the phenol function to the resin,the resin, which is obtained by method A and step 1, is mixedsuccessively with a solution that consists of 0.537 g (2.375 mmol) ofbenzoic acid anhydride and 2 ml of dichloromethane and a solution thatconsists of 0.015 g (0.119 mmol) of dimethylaminopyridine, 0.203 ml(0.154 g, 1.188 mmol) of ethyldiisopropylamine and 0.5 ml ofdichloromethane. Then, the suspension is shaken out at room temperature.After 18 hours, the resin is filtered off, washed six times with 2.5 mleach of dichloromethane (2 minutes) and once with 2.5 ml of diethylether (2 minutes) and dried in a vacuum on phosphorus pentoxide. 0.3085g of substituted resin, which is suspended in absolute dichloromethanefor 15 minutes and then is thoroughly filtered, is obtained.

Step 2

For cleavage, the resin is mixed with 2.5 ml of trifluoroaceticacid/dichloromethane solution (15/85), shaken for 30 minutes at roomtemperature, filtered and shaken again with 2.5 ml of trifluoroaceticacid/dichloromethane solution (15/85), filtered and finally extractedfour times with 2.5 ml of dichloromethane in each case. The combinedfiltrates or extracts are taken up with 10 ml of distilled water and setat pH 6 with sodium bicarbonate. The phases are separated, and theaqueous phase is extracted three times with 10 ml of dichloromethane.The combined organic extracts are washed twice with 10 ml each ofsaturated sodium chloride solution, dried on sodium sulfate, filteredand concentrated. The purification of the crude product (0.078 g) iscarried out by means of column chromatography (10 g of silica gel, ethylacetate/petroleum ether=2/1). After concentration by evaporation anddrying under high vacuum, 0.078 g of a colorless foam is obtained thatis 95% pure according to HPLC analysis. The colorless foam can bepurified by recrystallization from diethyl ether at −22° C. (deep freezefrom the refrigerator).

Yield: 0.059 g (0.056, 0.0125 mmol, thus a concentration of 0.41 mmol/g,61% of theoretical maximum concentration² is calculated), colorless foam(M_(w)447.5)²0.67 mmol/g=0.95 mmol/g/(1 g+1 g*0.95 mol/g*(447.5 g/mol−18 g/mol)/1000

TLC: R_(f)=0.29 (ethyl acetate/petroleum ether=1/1)

Melting point: 158-159° C. (diethyl ether)

¹H-NMR: (200.13 MHz, d₆-DMSO)

δ 7.99 (d, J=6.5 Hz, 2H), 7.38-7.71 (m, 3H), 6.39-6.63 (m, 3H),5.73-6.17 (m, 2H), 5.47 (t, J=4.3 Hz, 1H), 5.04-5.33 (m, 2H), 4.00-4.72(m, 6H), 2.60-2.89 (m, 1H), 2.55 (bd, J=18.6 Hz, 1H), 2.25 (bd, J=15.7Hz, 1H), 1.70-1.93 (m, 2H)

¹³C-NMR: (50.32 MHz, d₆-DMSO)

δ 165.4 (s), 154.6 and 154.4 (s), 146.3 (s), 141.3 (s), 133.5 (d), 133.3(d), 133.2 (d), 131.8 (d), 131.5 (s), 130.2 (s), 129.5 (d), 128.6 (d),128.0 (s), 122.2 (d), 120.4 and 120.0 (d), 117.0 and 116.1 (t), 115.0(d), 84.7 (d), 65.2 and 65.0 (t), 63.8 (d), 51.0 and 50.5 (t), 48.0 (s),45.1 and 44.7 (t), 37.3 and 36.4 (t), 27.4 (t)

HPLC: t_(Ref)=21.41 minutes, 95.1% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5 μm, 285 nm, 1 ml/minute, acetonitrile/20 mmol of Cl₃CCO₂Hin H₂O (15/85 for 5 minutes, 15/85 60/40 in 12 minutes, 60/40 for 5minutes, v/v)

(CK-63-1)

The resin, which is obtained by method B and step 1, is reactedanalogously to step 1 with benzoic acid anhydride, and after dryingunder vacuum, 0.3004 g of the substituted resin is obtained. Thecleavage of the product and the aqueous working-up are carried outanalogously to step 2. After the concentration by evaporation and thedrying in a vacuum, 0.070 g of crude product, which is purified by meansof column chromatography (10 g of silica gel, ethyl acetate/petroleumether=2/1), is obtained. After concentration by evaporation and dryingunder high vacuum, 0.051 g of a colorless foam, which is 93% pureaccording to HPLC analysis, is obtained.

Yield: 0.051 g (0.047 g, 0.0106 mmol, thus a concentration of 0.35mmol/g, 52% of the theoretical maximum concentration³, is calculated),colorless foam (M_(w)=447.5)³0.67 mmol/g=0.95 mmol/g/(1 g+1 g*0.95 mol/g*(447.5 g/mol−18g/mol)/1000)

HPLC: t_(Ref)=21.42 minutes, 92.7% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5 μm, 285 nm, 1 ml minute, acetonitrile/20 mmol of Cl₃CCO₂Hin H₂O (15/85 for 5 minutes, 15/85→60/40 in 12 minutes, 60/40 for 5minutes, v/v)

EXAMPLE 163 Synthesis of the Solid Phase/Manual

EXAMPLE 163 Steps 1-7 Immobilization of(4aR,6S,8aR)-3-Methoxy-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benazepin-6-olon a Hydroxymethyl-Polystyrene Resin (Merrifield Resin)

Method A (CK-4.1-1) Steps 1-2 and 5-7

5.000 g (5.2 mmol) of hydroxymethyl-Merrifield resin⁴ is stirred in athree-neck glass reactor with a frit that is recessed in the bottom anda KPG stirrer in 60 ml of dichloromethane for one hour (300 s⁻¹). Afterfiltering, the suspension is mixed with a solution of 2.373 g (20.8mmol) of glutaric acid anhydride, 4.45 ml (3.362 g, 26.0 mmol) ofethyldiisopropylamine in 30 ml of absolute dichloromethane. Thesuspension is stirred at room temperature for ten hours, filtered,washed once with 50 ml of dichloromethane, once with 50 ml of methanoland three times with 50 of dichloromethane in each case. The resin isthen dried in a vacuum.⁴Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG

4.385 g of the 4-carboxy-1-oxobut-1-yloxymethyl-Merrifield resin that isthus produced is suspended for 30 minutes in 50 ml of absolutedichloromethane while being stirred, and it is filtered. Then, 4.569 g(12.23 mmol) of N-tert-butoxycarbonylnorgalanthamine and 0.249 g (2.04mmol) of dimethylaminopyridine, both dissolved in 15 ml ofdichloromethane, and 2.10 ml (1.582 g, 12.23 mmol) ofethyldiisopropylamine, dissolved in 5 ml of dichloromethane, are added.While being stirred, a solution that consists of 1.89 ml (1.544 g, 12.23mmol) of diisopropylcarbodiimide and 5 ml of dichloromethane is added indrops within five minutes at room temperature. After 24 hours, the resinis filtered off, washed with 40 ml of methanol and filtered. Then, theresin is washed six times with 40 ml of dichloromethane in each case (5minutes) and dried in a vacuum.

The resin is mixed with 42 ml of absolute dichloromethane and 3 ml ofanisole and stirred for 30 minutes (150 s¹). Then, while being stirred(300 s¹), 15 ml of trifluoroacetic acid is added within 15 minutes.Then, the suspension is stirred for 60 minutes (150 s¹), filtered andwashed with dichloromethane (2×40 ml, 5 minutes), withdichloromethane/dimethylformamide/triethylamine (5/4/1) (3×40 ml, 5minutes) and finally with dichloromethane (5×40 ml, 5 minutes). Afterdrying in a vacuum, 4.353 g of resin is obtained.

To determine the concentration, 0.2384 g of resin in 3 ml ofdimethylformide is suspended in a polyethylene frit that can be sealedon both sides. After filtering, the resin is shaken in a solution thatconsists of 177 μl (0.191 g, 1.875 mmol) of acetic acid anhydride, 180μl (0.136 g, 1.050 mmol) of ethyldiisopropylamine and 2 ml ofdimethylformamide for nine hours at room temperature. After washing(dimethylformamide (3×2.5 ml, 2 minutes) and tetrahydrofuran/methanol(4/1) (5×2.5 ml, 2 minutes), the resin shows no reaction with thechloranil test. The polymer is suspended in a 0.3 M sodium methanolatesolution in tetrahydrofuran/methanol (4/1). The resin is shaken for 8hours at room temperature, filtered and extracted withmethanol/dichloromethane (1/1, 3×2.5 ml) and with dichloromethane (3×2.5ml). The combined filtrates are neutralized with methanolic hydrochloricacid. The solution is diluted with about 10 ml of dichloromethane,washed with 25 ml of saturated sodium bicarbonate solution, 1Nhydrochloric acid and saturated sodium chloride solution in each case,dried on sodium sulfate, filtered and concentrated. The purification iscarried out by means of column chromatography (10 g of silica gel,diethyl ether/ethanol=100/15). After concentration by evaporation anddrying under high vacuum, 0.028 g of a yellowish foam, which contain 10%other contaminants according to HPLC analysis, is obtained.

Yield: 0.025 g (0.080 mmol. A concentration of 0.34 mmol/g, 45% of thetheoretical maximum concentration⁵ thus is calculated), yellowish foam(M_(w)=315.4)⁵0.75 mmol/g=1.04 mmol/g/(1 g+1 g*1.04 mol/g*(387.4 g/mol=18g/mol)/1000)

TLC: R_(f)=0.29 (diethyl ether/ethanol=100/15)

IR: KBr

v (cm⁻¹) 3551 (v), 3305 (bm), 2926 (m), 2864 (v) 1650 (m), 1615 (s),1443 (m), 1257 (m), 1070 (m)

¹H-NMR: (200.13 MHz, CDCl₃, TMS) δ 6.54-6.89 (m, 2H), 5.75-6.09 (m, 2H),5.14-5.33 (m, 0.3H), 4.32-4.74 (m, 3.3H), 4.12 (bs, 1H), 3.86-4.00 (m,0.3H), 3.81 and 3.79 (s, 3H), 3.56-3.76 (m, 0.8H), 3.23 (bt, J=12.6 Hz,0.8H), 2.67 (bd, J=15.9 Hz, 1H), 2.38 (bs, 0.7H), 2.06 (m, 3H),1.62-2.00 (m, 3H),

HPLC: t_(Ref)=13.9 minutes, 89.8% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5 μm, 285 nm, 1 ml/minute, acetonitrile/20 mmol of Cl₃CCO₂Hin H₂O (05/95 for 5 minutes, 05/95→60/40 in 10 minutes, 10/40 for 10minutes, v/v, pH 10)

Method B (CK-43-2), Steps 1 and 3-7

3.500 g (3.64 mmol) of hydroxymethyl-Merrifield resin⁶ is reactedanalogously to the method that is described under method A with 1.661 g(14.6 mmol) of glutaric acid anhydride, 3.15 ml (2.378 g, 18.39 mmol) ofethyldiisopropylamine and 0.044 g (0.364 mmol) of dimethylaminopyridinein 20 ml of absolute dichloromethane. After washing, the resin isstirred successively with a solution that consists of 3.15 ml (2.378 g,18.39 mmol) of ethyldiisopropylamine, and 10 ml of absolutedichloromethane and with a solution that consists of 1.34 ml (1.317 g,10.92 mmol) of pivaloyl chloride and for nine hours at room temperature.After washing (dichloromethane (4×30 ml, 5 minutes), tetrahydrofuran (30ml, 5 minutes) and dichloromethane (2×30 ml, 5 minutes), the resin issuccessively treated with 4.061 g (10.87 mmol) ofN-tert-butoxycarbonylnorgalanthamine and 0.222 g (1.82 mmol) ofdimethylaminopyridine, both dissolved in 15 ml of dichloromethane, and3.15 ml (2.378 g, 18.39 mmol) of ethyldiisopropylamine, dissolved in 15ml of dichloromethane. After 24 hours at room temperature, the solutionis filtered off, and the resin is mixed with 40 ml of a dry solutionthat consists of methanol and dichloromethane, and it is stirred for tenminutes at room temperature. After filtering, six cycles of washing withdichloromethane and drying in a vacuum, the resin is washed and driedwith 40 ml of trifluoroacetic acid/dichloromethane/anisole (25/70/5)analogously to method A. 4.145 g of a yellow resin is obtained. 0.2214 gof the resin is reacted to determine the concentration analogously tothe method, and it is purified. 0.024 g of a yellowish foam, which is90% pure according to HPLC analysis, is obtained.⁶Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG

Yield: 0.022 g (0.069 mmol. This corresponds to a concentration of 0.31mmol/g, 41% of the theoretical maximum concentration).

HPLC: t_(Ref)=14.4 minutes, 89.0% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5 μm, 285 nm, 1 ml/minute, acetonitrile/20 mmol of Cl₃CCO₂Hin H₂O (05/95 for 5 minutes, 05/95→60/40 in 10 minutes, 60/40 for 10minutes, v/v, pH 10)

EXAMPLE 163 Steps 8-13

SPH-1528

1,2N—P-METHOXYBENZOYL-PHENYLALANYL-PHENYLALANINE-((4AS,6R,8AS)-6-HYDROXY-3-METHOXY-5,6,9,10-TETRAHYDRO-4AH-[[1]BENZOFURO[3A,3,2-EF][2]BENZAZEPINE-11(12H)—YL)-AMIDE(CK-47-1)

0.245 g (0.076 mmol) ofN-tert-butoxycarbonylnorgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifieldresin is steeped twice in a 5-ml-polyethylene frit that is sealed onboth sides for 15 minutes in 3 ml of dimethylformamide, and afterfiltering, it is suspended in a solution of 0.065 g (0.169 mmol) ofFmoc-phenylalanine and 0.062 g (0.169 mmol) of2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in1 ml of dimethylformamide each, and it is shaken for five minutes atroom temperature. Then, 58 μl (0.044 g, 0.338 mmol) ofethyldiisopropylamine in 0.5 ml of dimethylformamide is added. Thesuspension is shaken at room temperature for 3 hours. The resin iswashed six times with dimethylformamide (1 minute, 2.5 ml) and suspendedin a 20% piperidine solution in dimethylformamide for two and tenminutes in each case at room temperature. After six washing cycles withdimethylformamide (1 minute, 2.5 ml), the resin is reacted analogouslyto the first peptide coupling step with 0.065 g (0.169 mmol) ofFmoc-phenylalanine and 0.062 g (0.169 mmol) of2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in1 ml of dimethylformamide in each case and 58 μl (0.044 g, 0.338 mmol)of ethyldiisopropylamine in 0.5 ml of dimethylformamide, washed withdimethylformamide, shaken in 20% piperidine-dimethylformamide solutionand in turn washed six times with dimethylformamide (1 minute, 2.5 ml).Then, solutions of 0.065 g (0.169 mmol) of Fmoc-Phe-OH in 1 ml ofdimethylformamide, 0.062 g (0.169 mmol) of2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate in1 ml of dimethylformamide and 58 μl (0.044 g, 0.338 mmol) ofethyldiisopropylamine in 0.5 ml of dimethylformamide are addedsuccessively, and the suspension is shaken for 30 minutes at roomtemperature. The Kaiser test indicates complete reaction. Then, it iswashed analogously to the above-described procedure, suspended inpiperidine-dimethylformamide solution and washed in turn withdimethylformamide. After renewed successive addition of 0.026 g (0.169mmol) of p-methoxybenzoic acid in 1 ml of dimethylformamide, 0.062 g(0.169 mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate in 1 ml of dimethylformamide and 58 μl (0.044 g, 0.338mmol) of ethyldiisopropylamine in 0.5 ml of dimethylformamide, the resinis shaken overnight, since the Kaiser test was not unambiguous after 30minutes because of a green-bluish staining. The resin is filtered,washed three times with dimethylformamide, five times withdichloromethane and with methanol and then dried in a vacuum. The resin(0.251 g) is suspended for 30 minutes in THF, filtered and suspended ina solution that consists of 0.250 g (1.39 mmol) of 30% sodiummethanolate-methanol solution and 2.5 ml of tetrahydrofuran/methanol(4/1). After eight hours, the solution is filtered off, and the resin isextracted six times with 3 ml of dichloromethane/methanol in each case.The combined filtrates are neutralized with 106 μl (0.158 g, 1.39 mmol)of trifluoroacetic acid, concentrated and separated with preparativethin-layer chromatography (silica gel, chloroform/methanol=100/5). Theproduct-containing silica gel fraction is extracted withchloroform/methanol (9/1), and the combined extracts are filteredrepeatedly with a filter (pore diameter 0.2 μm), concentrated byevaporation and dried in a vacuum.

Yield: 0.041 g (0.029 g, 0.041 mmol, 53%), rose-colored wax(M_(w)=701.8). The product contains a by-product (0.006 g, 0.008 mmol,10%) that is a diastereomer of the main product according to LC/MS.

TLC: R_(f)=0.43 (chloroform/methanol=20/1)

HPLC: t_(Ref)=2.7 minutes, 70.4% (Phenomenex Luna column, 3.0 mm×50 mm,RP-18, 3.0 μm, 0.5 ml/minute, 285 nm, methanol/20 mmol of Cl₃CCO₂H inH₂O (30/70 v/v)

LC/MS: t_(Ref)=30.6 minutes, 73%, (Phenomenex Luna column, 3.0 mm×50 mm,RP-18, 3.0 μm, 0.5 ml/minute, methanol/H₂O (5/95 v/v for 2 minutes,5/95→40/60 v/v in 15 minutes, 40/60 v/v for 5 minutes)

APCI-PI-MS

702 (56), 421 (100), 274 (6), 256 (13)

APCI-NI-MS

700

t_(Ref)=35.6 minutes, 8%, (diastereomeric by-product)

APCI-PI-MS

702 (56) 421 (100), 274 (6), 256 (13)

APCI-NI-MS

700

1.3 1.4 EXAMPLES 163-167 Synthesis on Robots 1.5 1.6N—P-CARBOXYL-DIPEPTOYL-((4AS,6R,8AS)-6-HYDROXY-3-METHOXY-5,6,9,10-TETRAHYDRO-4AH-[1BENZOPURO[3A,3,2-EF][2]BENZAZEPINE-11(12H)—YL)AMIDE(CK-59-1)

In each case, 0.300 g (0.102 mmol) ofnorgalanthamine-6-yloxy-1,5-dioxopentyloxymethyl-Merrifield resin isintroduced into polyethylene reactors with frits of a synthesis robot(Syro II MultiSynTech) and mixed with 3 ml of absolutedimethylformamide. After five minutes of standing, the suspensions arestirred at intervals for 25 minutes at 23° C. All subsequent operationsare carried out at this temperature. Then, the resins are washed oncewith 3 ml of dimethylformamide and mixed successively with a solutionthat consists of 0.119 g (0.306 mmol) of Fmoc-phenylalanine or 0.117 g(0.306 mmol) of N-Fmoc-o-tert-butylserine and 1.5 ml ofdimethylformamide and with a solution that consists of 0.112 g (0.306mmol) of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate and 1 ml of dimethylformamide. Then, the resinsuspensions are stirred for five minutes. Then, 105 μl (0.079 g, 0.612mmol) of ethyldiisopropylamine in 0.5 ml of dimethylformamide is added.The suspensions are stirred for 3 hours, suctioned off for two minutesand in each case mixed with a solution that consists of 241 μl (0.260 g,2.550 mmol) of acetic anhydride, 437 μl (0.330 g, 2.550 mmol) ofethyldiiospropylamine and 3 ml of dimethylformamide. After 15 minutes ofstirring and two minutes of filtering, the resins are washed six timeswith dimethylformamide (3 ml, 2 minutes), and suspended or stirred in a20% piperidine solution in dimethylformamide for six and 15 minutes ineach case. After six cycles of washing with dimethylformamide (2minutes, 3 ml), the resins are reacted analogously to the first peptidecoupling step with Fmoc-phenylalanine or N-Fmoc-O-tert-butylserine, theunreacted amine groups are masked with acetic anhydride, and theFmoc-protective group is cleaved off with 20% piperidine-dimethylformidesolution. It is then washed analogously to the above-describedprocedure, mixed with a solution that consists of 0.047 g (0.306 mmol)of p-methoxybenzoic acid or 0.038 g (0.306 mmol) of isonicotinic acid in2.5 ml of dimethylformamide and stirred for five minutes. Then, in eachcase, solutions of 48 μl (0.039 g, 0.306 mmol) ofdiisopropylcarbodiimide 241 μl and 0.5 ml of 1,2-dichloroethane areadded. It is stirred for three hours. The resins are filtered (2minutes), washed three times with dimethylformamide (2 minutes, 3 ml),six times with dichloromethane (2 minutes, 3 ml), dried for ten minutesat 40° C., suctioned off and then dried in a vacuum on phosphoruspentoxide. The Kaiser test is negative in all resins (0.250 to 0.377 g).

The resins that contain O-tert-butyl-protected serine radicals are mixedsuccessively with 1 ml of dichloromethane, 0.125 ml of phenol, 0.125 mlof anisole and 3.75 ml of trifluoroacetic acid, and it is stirred forthree hours at room temperature. Then, the solutions are filtered off,and the resins are washed three times with dichloromethane (2 minutes, 3ml), three times with dichloromethane/ethyldiisopropylamine (95/5, 2minutes, 3 ml), three times with dichloromethane (2 minutes, 3 ml) ineach case, and three times with tetrahydrofuran (2 minutes, 3 ml) anddried under reduced pressure.

The resins are transferred to 5-ml polyethylene frits that are sealed onboth sides, suspended for 30 minutes in THF, filtered and suspended in asolution that consists of 0.092 g (0.028 g, 0.510 mmol) of 30% sodiummethanolate-methanol solution and 3 ml of tetrahydrofuran/methanol(4/1). After six hours, the solution is filtered off, and the resin isextracted five times with 3 ml of tetrahydrofuran/methanol (4/1) in eachcase. The combined filtrates are neutralized with Dowex 50W (one spatulatip full) and NaHCO₃ (one spatula tip full). The suspensions arefiltered on some Celite, and the filter Celite is flushed twice with 5ml of dichloromethane. The filtrates are concentrated and purified withpreparative thin-layer chromatography (mobile solvent:chloroform/methanol=(10/1) for CK-49-1-IPP-3, CK-59-MPP-1, CK-59-IPP-2,CK-59-AcPP-3, chloroform/methanol=(4/1) for CK-59-IPP-4 andchloroform/methanol=(6/1) for CK-59-MPP-5). The product-containingsilica gel fractions are extracted with chloroform/methanol (9/1) andfiltered. The extracts that are concentrated by evaporation are filteredrepeatedly with a filter (pore diameter 0.2 μm), further concentrated byevaporation and dried in a vacuum.

HPLC: Phenomenex Synergi Polar-RP-column, 4.6 mm×150 mm, 4.0 μm, 1.0ml/minute, methanol/20 mm of Cl₃CCO₂H in H₂O (20/80 for 5 minutes,20/80→80/20 in 20 minutes, 80/20 for 10 minutes, v/v)

LC/MS Phenomenex Luna column, 3.0 mm×50 mm, RP-18, 3.0 μm, 0.8ml/minute, methanol/H₂O (10/90 for 2 minutes, 10/90→100/0 in 15 minutes,100/0 for 5 minutes, v/v)

Result Aminosäure Beispiel SPH-Nummer 1 und 2 Carboxylrest 3 R_(f)-WertCK-59- 163 SPH-1528 Ph, Ph 4-MeOC₆H₄ 0.60 (CHCl₃/CH₃OH = 10/1) MPP-1-1CK-59- Ph, Ph 4-MeOC₆H₄ 0.45 (CHCl₃/CH₃OH = 10/1) MPP-1-2 CK-49-1- 166SPH-1528 Ph, Ph p-NC₅H₄ 0.40 (CHCl₃/CH₃OH = 9/1) IPP-3-1 CK-59- 164SPH-1528 Ph, Ph Me 0.52 (CHCl₃/CH₃OH = 10/1) AcPP-3-1 CK-59- Ph, Ph Me0.43 (CHCl₃/CH₃OH = 10/1) AcPP-3-2 CK-59-ISS- 165 SPH-1528 OH, OHp-NC₅H₄ 0.22 (CHCl₃/CH₃OH = 6/1) 4-1 CK-59-ISS- OH, OH p-NC₅H₄ 0.17(CHCl₃/CH₃OH = 6/1) 4-2 CK-59- 167 SPH-1528 OH, OH 4-MeOC₆H₄ 0.37(CHCl₃/CH₃OH = 6/1) MSS-5-1 CK-59- OH, OH 4-MeOC₆H₄ 0.27 (CHCl₃/CH₃OH =6/1) MSS-5-2[Key to Table:]Beispiel = ExampleSPH-Nummer = SPH NumberAminosäure 1 und 2 = Amino acid 1 and 2Carboxylrest 3 = Carboxyl radical 3R_(f)-Wert = R_(f) value

HPLC (t_(Ref), Ausbeute und Beispiel Code Reinheit) LC/MS Bemerkung 163CK-59- 29.90 min t_(Ref) = 10.90 min 0.021 g (0.015 g, MPP-1-1 (71%)APCI, Neg 0.021 mmol, 21%) 700 (100) APCI, Pos 702 (63), 684 (8), 421(100), 274 (5), 256 (15) CK-59- 29.35 min t_(Ref) = 10.90 min 0.014 g(0.003 g, MPP-1-2 (24%) APCI, Neg 0.005 mmol, 700 (100), 682 (7), 606(13) 5%); APCI, Pos racemisiertes 702 (63), 684 (26), 608 (28), 421(100), 274 Produkt (11), 256 (19) 166 CK-49-1- 24.91 min t_(Ref) = 20.22min 0.067 g (0.040 g, IPP-3-1 (59%) APCI, Neg 0.059 mmol, 58%) 671 (100)APCI, Pos 673 (100), 655 (18), 421 (7), 274 (6), 256 (53) 164 CK-59-26.50 min t_(Ref) = 10.08 min 0.058 g (0.029 g, AcPP-3-1 (50%) APCI, Neg0.048 mmol, 47%) 608 (100) APCI, Pos 610 (100), 592 (15), 421 (17), 274(8), 256 (40) CK-59- 26.09 min t_(Ref) = 10.01 min 0.019 g (0.011AcPP-3-2 (54%) APCI, Neg mmol, 0.017 608 (100) mmol, 17%); APCI, Posracemisiertes 610 (100), 592 (24), 421 (20), 274 (18), 256 Produkt (69)165 CK-59- 14.67 min t_(Ref) = 7.49 min 0.009 g (0.008 g, ISS-4-1 (92%)APCI, Neg 0.015 mmol, 15%) 551 (100), 533 (26), 521 (17), 491 (6) APCI,Pos 553 (100), 535 (36), 403 (6), 385 (9), 256 (100) CK-59- 15.90 mint_(Ref) = 7.63 min 0.004 g (0.002 g, ISS-4-2 (48%) APCI, Neg 0.003 mmol,551 (100), 533 (25), 521 (19), 491 (5) 3%); APCI, Pos racemisiertes 553(100), 535 (70), 517 (7), 274 (9), 256 Produkt (57) 167 CK-59- 21.12 mint_(Ref) = 8.35 min 0.013 g (0.007 g, MSS-5-1 (27%) APCI, Neg 0.012 mmol,und 580 (100), 562 (17), 550 (15), 520 (6) 12%); 21.57 min APCI, Posracemisiertes (26%) 582 (49), 564 (43), 546 (67), 361 (100), 256 Produkt(55) t_(Ref) = 8.49 min APCI, Neg 580 (100), 562 (21), 550 (16), 520 (9)APCI, Pos 582 (43), 564 (47), 546 (51), 361 (100), 256 (64) CK-59- 21.27min t_(Ref) = 8.39 min 0.008 g (0.002 g, MSS-5-2 (10%) und APCI, Neg0.003 mmol, 21.58 580 (100) 3%); (15%) t_(Ref) = 8.64 min racemisiertesAPCI, Neg Produkt 580 (100), 562 (35), 550 (14) APCI, Pos 582 (63), 564(77), 546 (77), 361 (100), 256 (63)[Key to Table:]Beispiel = ExampleHPLC (t_(Ref), Reinheit) = HPLC (t_(Ref), purity)Ausbeute und Bemerkung = Yield and Remarksracemisiertes Product = Racemized product

EXAMPLE 167b

SPH-1543

As a by-product,N-acetyl-phenylalanine-((4aS,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzo-furo-[3a,3,2-ef]-[2]benzazepine-11(12H)-yl)amidewas obtained:

HPLC (t_(Ret), Ausbeute und Code Reinheit) LC/MS und Ri-Wert BemerkungCK-59- 23.49 min t_(Ret) = 9.37 min 0.036 g (0.031 g, IPP-2-1 (67%)APCl, Neg 0.077 mmol, 76 461 (100) %) APCl, Ros 463 (100), 445 (8), 274(17), 256 (31) 0.50 (CHCl₃/CH₃OH = 10/1) CK-59- 23.60 mint_(Ret = 9.40 min) 0.012 g (0.008 g, IPP-2-2 (66%) APCl Neg 0.17 mmol,17 461 (100) %); APCl, Pos racemisiertes 463 (100), 445 (17), 274 (32),256 (60) Produkt 0.36 (CHCl₃/CH₃OH = 10/1)[Key to Table:]HPLC (t_(Ref), Reinheit) = HPLC (t_(Ref), purity)LC/MS und R_(f)-Wert = LC/MS and R_(f) valueAusbeute und Bemerkung = Yield and remarksracemisiertes Produkt = Racemized product

EXAMPLE 170

SPH-1371

(4aa,6b,8aR*)-4a,5,9,10,11,12-Hexahydro-3-mothoxy-11-[3-(1-piperidinyl)propyl]-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol,Dihydrobromide, Dihydrate

Production from the free base by treatment with Hbr/EtOH [a]_(D)²⁰=−92.5° (c 0.24, H₂O)

General Instructions—“Thiophene Derivatives”

EXAMPLES 171-172

1.1 equivalents of norgalanthamine and 1 equivalent of the correspondingthienyl-halide were heated to reflux temperature together with 3equivalents of fine-powder, anhydrous K₂CO₃ in dry acetonitrile (10% byweight of solution) for 24 hours. Complete conversion was examined bymeans of TLC.

After the solution was cooled, it was filtered, and the K₂CO₃ residuewas washed several times with dry acetonitrile while being monitored byTLC. The crude product that was obtained after concentration byevaporation was purified by means of flash chromatography,

EXAMPLE 171

SPH-1490

6,7-Dihydro-5-(4-((4aS,6R,8aS)-6-hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-butyl)-benzo[b]thiophene-4(5H)-one

C₂₈H₃₃NO₄S (479.64) SPH-1490

Norgalanthamine: 500 mg (1.83 mmol) 5 (4-bromobutyl)-6,7-dihydro- 479 mg(1.67 mmol) benzo[b]thiophene-4(5H)-one: K₂CO₃: 693 mg (5.01 mmol) about4 ml of acetonitrile

Crude product: 450 mg

Flash chromatography: Ethyl acetate:triethylamine 100:2

Yield: 440 mg (50%) of a light yellow powder

¹H (400 MHz, CDCl₃)

δ 7.34 (d, J=5.26, 1H), 7.04 (d, J=5.26, 1H), 6.66 (d, J=8.18, 1H), 6.62(d, J=8.18, 1H), 6.09 (m, 2H), 4.61 (m, 1H), 0.25-4.07 (m, 2H),3.92-3.84 (m, 1H), 3.84-3.79 (m, 1H), 3.80 (s, 3H), 3.46-3.56 (m, 1H),3.30-3.18 (m, 1H), 3.13-3.03 (m, 1H) 3.02-2.91 (m, 1H), 2.73-2.65 (m,1H), 2.64-2.47 (m, 2H), 2.45-2.36 (m, 1H), 2.32-2.23 (m, 1H), 2.11-1.83(m, 4H), 1.63-1.09 (m, 6H)

¹³C (100 MHz, CDCl₃):

δ195.2 (s), 154.8 (2*s), 145.8 (s), 144.4 (s), 136.8 (s) 132.9 (s),127.9 (d), 126.4 (d), 125.1 (d), 123.2 (d), 122.4 (d), 111.3 (d), 88.6(d), 61.9 (d), 58.1 (t), 55.9 (q), 51.4 (t), 51.3 (t), 48.2 (s), 46.2(d), 29.9 (t), 29.5 (t), 28.9 (t), 28.8 (t), 28.5 (t), 24.8 (t), 24.2(t)

EXAMPLE 172

SPH-1491

6,7-Dihydro-5-(5-((4aS,6R,8aS)-6-hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-pentyl)-benzo[b]thiophen-4(5H)-one

C₂₉H₃₅NO₄S (493.67) SPH-1491

Norgalathamine: 200 mg (0.73 mmol)5-(5-bromopentyl)-6,7-dihydro-benzo[b]- 201 mg (0.67 mmol)thiophen-4(5H)-one: K₂CO₃: 277 mg (2.00 mmol) about 4 ml of acetonitrile

Crude product: 430 mg

Flash chromatography: ethyl acetate:triethylamine=100:2

Yield: 240 mg (66.3%) of a light yellow powder

¹H NMR (400 MHz, CDCl₃)

δ 7.35 (d, J=5.2 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 6.64 (d, J=8.1 Hz,1H), 6.61 (d, J=8.1 Hz, 1H), 6.05 (d, J=10.2 Hz, 1H), 5.99 (dd, J=10.2,4.6 Hz, 1H), 4.60 (m, 1H), 3.83 (d, J=15.2, 1H), 4.14-4.10 (m, 1H), 3.83(d, J=15.2 Hz, 1H), 3.81 (s, 3H), 3.41-3.31 (m, 1H), 3.22-3.14 (m, 1H),3.07 (dt, J=17.2, 5.2 Hz, 1H), 2.96 (ddd, J=17.2, 9.1, 4.7 Hz, 1H),2.70-2.62 (m, 1H), 2.56-2.34 (m, 4H), 2.26 (m, 1H), 2.10-1.8 (m, 4H),1.61-1.21 (m, 8H)

¹³C NMR: (100 MHz, CDCl₃)

δ 195.7 (s), 155.1 (2*s), 146.2 (s), 144.5 (s), 137.3 (s), 133.5 (s),128.0 (d), 127.3 (d), 125.5 (d), 123.6 (d), 122.5 (d), 111.5 (d), 89.1(d), 62.5 (d), 58.1 (t), 56.3 (q), 51.3 (t), 48.8 (s), 46.7 (d), 33.2(t), 30.3 (t), 30.0 (t), 29.9 (t), 29.4 (t), 27.8 (t), 27.6 (t), 27.5(t), 24.6 (t)

General Instructions—“Azacycloalkyl Derivatives”

EXAMPLES 173-176

One equivalent of norgalanthamine and 3 equivalents of the correspondingaminoalkyl halide was heated to reflux temperature together with 3equivalents of fine-powder, dry K₂CO₃ in dry acetonitrile (about 10% byweight of solution) for 24 hours. Complete conversion was controlled bymeans of TLC.

After the solvent was distilled off, the remaining residue was dissolvedin 2N HCl. After two extraction cycles with diethyl ether, it was madealkaline with 10% NaOH solution and extracted exhaustively withchloroform. After drying on Na₂SO₄, it was concentrated by evaporationand purified by means of flash chromatography (CHCl₃:MeOH:NH₃=10:1:0.5).The indicated yields of the reactions relate to 500 mg (1.83 mmol) ofnorgalanthamine as a starting product and were determined according toflash chromatography.

EXAMPLE 173

SPH-1492

(4aS,6R,8aS)-3-Methoxy-1-(6-piperidin-1-yl-hexyl)-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol

C₂₇H₄₀N₂O₃ (440.63)

Yield: 161 mg (20%) of a yellowish oil

¹H (400 MHz, CDCl₃):

δ 6.66 (d, J=8.0 Hz, 1H), 6.62 (d, J=8.0 Hz, 1H), 6.10 (d, J=10.0 Hz,1H), 6.01 (dd, J=10.0, 5.4 Hz, 1H), 4.62 (m, 1H), 4.14 (m, 1H), 4.13 (d,J=15.6, 1H), 3.84 (s, 3H), 3.81 (d, J=15.6, 1H), 3.4-3.3 (m, 1H),3.2-3.15 (m, 1H), 2.69 (ddt, J=15.7, 3.4, 1.6 Hz, 1H), 2.55-2.25 (m,8H), 2.10-2.0 (m, 1H), 2.01 (ddd, J=12.9, 5.0, 2.6 Hz, 1H), 1.65-1.2 (m,16H)

¹³C (100 MHz, CDCl₃):

δ 146.2 (s), 144.4 (s), 133.6 (s), 129.9 (s), 127.9 (d), 127.4 (d),122.4 (d), 111.5 (d), 89.1 (d), 62.5 (d), 59.9 (t) 58.1 (t), 56.3 (q),54.9 (4*t), 51.9 (t), 48.8 (s), 33.3 (t) 30.3 (t), 28.0 (t), 27.9 (t),27.8 (t), 27.1 (t), 26.2 (t), 24.8 (t)

EXAMPLE 174

SPH-1493

(4aS,6R,8aS)-3-Methoxy-11-(6-(4-methylpiperazine)-1-yl-hexyl)-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol

C₂₇H₄₁N₃O₃ (455.65)

Yield: 208 mg (25%) of a yellowish oil

¹H (400 MHz, CDCl₃)

δ 6.66 (d, J=8.18, 1H), 6.61 (d, J=8.18, 1H), 6.09 (d, J=10.23, 1H), 6.0(dd, J=9.94, 4.97, 1H), 4.61 (m, 1H), 4.20-4.08 (m, 2H), 3.84 (s, 3H),3.80 (d, J=15.8, 1H), 3.40-3.30 (m, 1H), 3.23-3.10 (m, 1H), 2.73-2.63(m, 1H), 2.63-2.30 (m, 12H), 2.29 (s, 3H), 2.10-1.94 (m, 2H), 1.57-1.17(m, 10H)

¹³C (100 MHz, CDCl₃)

δ 146.2 (s), 144.4 (s), 133.6 (s), 129.9 (s), 127.9 (d), 127.4 (d),122.4 (d), 111.5 (d), 89.1 (d), 62.5 (d), 59.1 (t), 58.2 (t), 56.3 (q),55.5 (2*t), 53.6 (3*t), 51.9 (t), 48.8 (s), 46.5 (q), 33.3 (t), 30.4(t), 27.98 (t), 27.83 (t), 27.74 (t), 27.23 (t)

EXAMPLE 175

SPH-1494

(4aS,6R,8aS)-3-Methoxy-11-(6-[4-hydroxypiperidine)-1-yl-hexyl)-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol

C₂₇H₄₀N₂O₄ (456.63)

Yield: 200 mg (24%) of a yellowish oil

¹H (400 MHz, CDCl₃)

δ 6.64 (d, J=8.1 Hz, 1H), 6.59 (d, J=8.1 Hz, 1H), 6.07 (d, J=10.2 Hz,1H), 5.97 (dd, J=10.2, 4.9 Hz, 1H), 4.58 (m, 1H), 4.11 (m, 1H), 4.07 (m,1H), 3.81 (s+m, 4H), 3.71-3.61 (m, 1H), 3.35 (m, 1H), 3.15 (m, 1H),2.81-2.71 (m, 2H), 2.67 (d, J=15.4, 1H), 2.52-2.36 (m, 4H), 2.34-2.26(m, 2H), 2.20-2.08 (m, 2H), 2.06-1.94 (m, 2H), 1.93-1.84 (m, 2H),1.63-1.53 (m, 2H), 1.52-1.38 (m, 5H), 1.32-1.20 (m, 4H)

¹³C (100 MHz, CDCl₃):

δ 146.2 (s), 144.5 (s), 133.6 (s), 129.9 (s), 127.9 (d), 127.4 (d),122.4 (d), 111.5 (d), 89.1 (d), 62.5 (2*d), 58.9 (2*t), 58.2 (t), 56.3(q), 51.9 (2*t), 51.3 (t), 48.8 (s), 34.6 (t), 33.4 (t), 30.4 (t), 28.0(t), 27.8 (2*t), 27.7 (t), 27.3 (t)

EXAMPLE 176

SPH-1521

1-(6-((4aS,6R,8aS)-6-Hydroxy-3-methoxy-4a,5,9,10-tetrahydro-6H-benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)-hexyl)-piperidin-4-one

C₂₇H₃₈N₂O₄ (454.61)

Yield: 125 mg (15%) of a yellowish oil

¹H (400 MHz, CDCl₃):

δ 6.65 (d, J=8.18 Hz, 1H), 6.60 (d, J=8.18 Hz, 1H), 6.07 (d, J=10.8 Hz,1H), 5.99 (dd, J=10.8, 4.5 Hz, 1H), 4.60 (m, 1H), 4.18-4.08 (m, 2H),3.82 (s, 3H), 3.79-3.76 (m, 1H), 3.40-3.30 (m, 1H), 3.22-3.10 (m, 1H),2.74-2.68 (m, 4H), 2.67-2.62 (m, 1H), 2.53-2.34 (m, 8H), 2.09-1.93 (m,2H), 1.57-1.42 (m, 6H), 1.37-1.21 (m, 4H)

¹³C (100 MHz, CDCl₃)

δ 209.7 (s), 146.2 (s), 144.5 (s), 133.5 (s), 129.7 (s), 128.1 (d),127.4 (d), 122.4 (d), 111.5 (d), 89.0 (d), 62.4 (d), 58.1 (2*t), 57.9(2*t), 56.4 (q), 56.3 (t), 53.4 (t), 52.2 (t), 51.9 (t), 48.8 (s), 41.5(t), 33.4 (t), 30.4 (t), 27.9 (t), 27.8 (t), 27.7 (t)

EXAMPLE 180

SPH-1363

(4aS,6R,8aS)-6-hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)methyl-azodicarboxylicacid-di-tert-butyl ester (CK-24-2)

A solution that consists of 0.300 g (0.104 mmol) of galanthamine in 3 mlof dichloromethane is introduced at room temperature, mixed with 0.264 g(1.150 mmol) of di-tert-butylazodicarboxylate and stirred for four daysat room temperature. After concentration by evaporation in a rotaryevaporator, the residue (0.258 g) is purified by means of flashchromatography on silica gel (25 g, mobile solventdichloromethane/petroleum ether=2/3+4% triethylamine). After dryingunder high vacuum, 0.292 g of a white foam is obtained.

Yield: 0.292 g (0.56 mmol, 54%), colorless foam, (M_(w)=517.6)

TLC: R_(f)=0.71 (dichloromethane/methanol=9/1+2% concentrated NH₃solution)

Melting point: 59-62° C. (petroleum ether/dichloromethane=1/1+4%triethylamine)

IR: KBr

v (cm⁻¹) 3557 (v), 3340 (bm), 2932 (s), 2915 (s), 1726 (s), 1711 (s)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 6.49-6.66 (m, 2H), 6.39 (s, 0.6 H), 5.84-6.06 (m, 2H), 4.52 (s, 1H),4.35 (bs, 1H), 3.99-4.17 (m, 2H), 3.71-3.88 (m, 1H), 3.76 (s, 3H),3.07-3.40 (m, 2H), 2.61 (bd, J=15.7 Hz, 1H), 2.40 (bd, J=11.8 Hz, 0.3H),1.79-2.05 (m, 2H), 1.56-1.72 (m, 1H), 1.46 (s, 9H), 1.45 (s, 9H)

¹³C NMR: (50.32 MHz, CDCl₃, TMS)

δ 156.7 (s), 155.9 (s), 145.9 (s), 144.0 (s), 132.8 (d), 129.8 (s),127.6 (d), 126.7 (d), 121.5 (d), 111.1 (d), 88.5 (d), 68.9 (t), 62.4(t), 61.8 (t) 61.8 (d), 56.6 (t), 55.8 (q), 49.7 (t), 48.1 (s), 35.2(t), 29.8 (t), 14.32 (q), 14.26 (q)

LC/MS: t_(Ref)=9.56 minutes, (Zorbax SB column, 2.1 mm×30 mm, RP-18, 3μm, 0.5 ml/minute, methanol/H₂O (40/60→100/0 (v/v) in 2 minutes)

APCI-PI-MS

518 (100), 500 (25), 462 (9), 285 (13), 274 (11) 256 (26)

APCI NI-MS

516

EXAMPLE 181

SPH-1362

(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)methyl-azodicarboxylicacid diethyl ester (CK-21-3)

89 μl (0.100 g, 0.57 mmol) of diethylazodicarboxylate is added to asolution that consists of 0.150 g (0.52 mmol) of galanthamine in 2 ml ofdichloromethane, and the solution is stirred for 72 hours at roomtemperature. After concentration by evaporation in a rotary evaporator,the residue (0.258 g) is purified by means of flash chromatography onsilica gel (25 g, mobile solvent dichloromethane/petroleum ether=1/1+4%triethylamine). After drying under high vacuum, 0.168 g of a white foamis obtained.

Yield: 0.168 g (0.36 mmol, 70%), white foam, (M_(w)=461.6)

TLC: R_(f)=0.66 (dichloromethane/methanol=9/1+2% concentrated NH₃solution)

Melting point: 40-42° C. (petroleum ether/dichloromethane=1/1+4%triethylamine)

IR: KBr

v (cm⁻¹) 3553 (v), 3305 (m), 2981 (s), 2935 (s), 1742 (s), 1722 (s)

¹H-NMR (200.13 MHz, CDCl₃, TMS)

δ 6.77 (bs, 1H), 6.64 (d, J=8.3 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H),5.84-6.06 (m, 2H), 4.53 (s, 1H), 3.98-4.23 (m, 6H), 3.69-3.87 (m, 1H),3.76 (s, 3H), 3.01-3.42 (m, 2H), 2.66 (bd, J=15.7 Hz, 1H), 2.33 (bs,0.2H), 1.65-1.77 (m, 2H), 1.35-1.47 (m, 1H), 1.09-1.35 (m, 6H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 155.1 (s), 145.9 (s), 143.9 (s), 132.8 (d), 130.2 (s), 127.5 (d),126.9 (d), 121.4 (d), 111.1 (d) 81.2 (s), 80.9 (s), 69.5 (t), 61.9 (d),56.8 (t) 55.8 (q), 49.8 (t), 48.1 (s), 35.6 (t), 29.8 (t), 28.1 (1),28.0 (q)

LC/MS: t_(Ref)=8.08 minutes, (Zorbax SB column, 2.1 mm×30 mm, RP-18, 3μm, 0.5 ml/minute, methanol/H₂O (40/60→100/0 (v/v) in 2 minutes)

APCI-PI-MS

462 (100), 444 (32), 286 (34), 274 (12), 256 (29)

APCI-NI-MS

460Process for Synthesis of Norgalanthamine

Method A

20 g (70 mmol) of galanthamine is reacted with 14.206 g (0.07 mol) ofm-chloroperbenzoic acid (85%) in 350 ml of dichloromethane andsubsequent addition of 9.730 g (35 mmol) of Fe(II) SO₄*7H₂O in 100 ml ofmethanol. The reaction is terminated after 20 minutes with 200 ml of 2Nhydrochloric acid. After the slightly volatile solvent is distilled off,after the acids and bases are separated and after the I e(OH)_(x)precipitate is filtered off by means of a Hyflo nutsch, the filtrate isdried on Na₂SO₄, filtered and concentrated by evaporation. About 18 g ofthe crude product is obtained in the form of a yellow foam.

Working-up Variant 1 (CK-1-1)

The crude product (18.46 g) is taken up in about 200 ml of ethylacetate/methanol/triethylamine (90/10/2) while being heated slightly.During cooling, I e(OH)_(x) is again precipitated, which is filteredoff. The purification is carried out by means of MPLC chromatography(silica gel, h=25 cm, d=3.6 cm, v=300 nm) with an altered mobile solventmixture (ethyl acetate/methanol/triethylamine=95/5/2-90/10/2→80/20/2).The norgalanthamine content is only 68% according to an HPLCquantification (caffeine as an internal standard).

Yield: 10.34 g (38 mmol, 54%), yellowish, amorphous solid (M_(w)=273.3)

Working-up Variant 2 (CK-1-11)

The crude product (16.48 g) is dissolved in 100 ml of methanol, mixedwith a solution that consists of 12.86 g (102 mmol) of oxalic aciddihydrate in 100 ml of methanol and carefully heated to homogenize thesolution. Then, the solution is allowed to cool to room temperature andthen to cool to about 5° C., the crystallized product is filtered off,and the precipitate is washed with methanol. The combined methanolsolutions that are concentrated by evaporation are again subjected torecrystallization.

Yield: 16.108 g (43 mmol, 62%), colorless crystalline solid

Cld. for C₁₆H₁₉NO₃.C₂H₂O₄0.5 H₂O C, 58.06 H, 5.95 N, 3.76 Fnd. C, 57.91H, 5.88 N, 3.69Method B (CK-1-10)

2.000 g (6.96 mmol) of galanthamine and 0.981 g (10.44 mmol) of hydrogenperoxide-urea-adduct are stirred for two days in 25 ml ofdichloromethane and 5 ml of methanol at room temperature, then mixedwith 0.030 g of platinum/activated carbon and stirred for one hour atroom temperature. When the catalyst is added, a strong gas developmentcan be observed. Then, 0.967 g (3.48 mmol) of Fe(II) SO₄*7H₂O in 5 ml ofMeOH is added, and the brown suspension is vigorously stirred. Thereaction is terminated after 20 minutes with 50 ml of saturated NaHCO₃solution. The reaction solution is filtered by means of a Hyflo filteraid. The phases are separated, and the aqueous phase is extractedexhaustively with dichloromethane. The combined organic extracts arewashed with saturated NaHCO₃ solution (50 ml) and with saturated NaClsolution (50 ml), dried on Na₂SO₄, filtered and concentrated byevaporation. The crude product (1.925 g) is dissolved in 10 ml ofmethanol, mixed with a solution that consists of 1.332 g (10.6 mmol) ofoxalic acid dihydrate in 10 ml of methanol and carefully heated tohomogenize the solution. Then, the solution is allowed to cool to roomtemperature and then to about 5° C., the crystallized product isfiltered off, and the precipitate is washed with methanol. The combinedmethanol solutions that are concentrated by evaporation are againsubjected to recrystallization.

Yield: 1.010 g (2.7 mmol, 39%), colorless crystalline solid(M_(w)=371.4), according to HPLC 97%

Method C:

Demethylation of Norgalanthamine by Means of Diethylazodicarboxylate(CK-1-7)

178 μl (0.199 g, 1.144 mmol) of diethylazodicarboxylate is added to asolution that consists of 0.300 g (1.04 mmol) of galanthamine in 3 ml ofdichloromethane, and the solution is stirred for three days at roomtemperature. After concentration by evaporation in a rotary evaporatorat 40° C., the residue is dissolved in 5 ml of ethanol and 5 ml of 4Nhydrochloric acid and stirred at 80° C. for one and one-half hours. Thereaction is cooled to room temperature, and the solution is diluted with5 ml of water. The ethanol portion is distilled off in a rotaryevaporator, and the aqueous phase is extracted three times with 10 ml ofdiethyl ether in each case. The aqueous phase is set at pH 10-11 byadding sodium carbonate and sodium hydroxide, and it is extracted fourtimes with 20 ml of dichloromethane in each case. The combined phasesare washed with 40 ml of saturated common salt solution and dried onNa₂SO₄. After filtering and concentration by evaporation, the residue(0.268 g) is purified by means of MPLC on silica gel (60 g, mobilesolvent ethyl acetate/ethanol/triethylamine=19/1/0.4). After dryingunder high vacuum, 0.136 g of a yellowish foam is obtained.

Yield: 0.136 g (0.495 mmol, 48%), white-yellowish foam, (M_(w)=273.3),HPLC identical to a reference sample

HPLC: t_(Ref)=3.79 minutes, 96.3% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5 μm, 250 nm, 1 ml/minute, acetonitrile/20 mmol oftrichloroacetic acid in H₂O (15/80 v/v)

Method D:

Demethylation of Norgalanthamine by Means ofDi-tert-butylazodicarboxylate (CK-1-6)

0.300 g (1.04 mmol) of galanthamine and 0.264 g (1.144 mmol) ofdi-tert-butylazodicarboxylate in 3 ml of dichloromethane are reactedanalogously to the above-described procedure for three days at roomtemperature, concentrated by evaporation and stirred in 5 ml of ethanoland 5 ml of 4N hydrochloric acid for 30 minutes at 80° C. The reactionis cooled to room temperature, and the solution is diluted with 5 ml ofwater. After the aqueous working-up, the residue (0.259 g) is purifiedby means of MPLC on silica gel (60 g, mobile solvent ethylacetate/ethanol/triethylamine=19/1/0.4). After drying under high vacuum,0.132 g of a white-yellowish foam is obtained.

Yield: 0.132 g (0.48 mmol, 46%), white-yellowish foam, (M_(w)=273.3),HPLC identical to a reference sample

HPLC: t_(Ref)=3.74 minutes, 100% (Merck Purospher column, 4.0 mm×125 mm,RP-18e, 5 μm, 250 nm, 1 ml/minute, acetonitrile/20 mmol oftrichloroacetic acid in H₂O (15/80 v/v)

Method E:

Saponification of(4aS,6R,8aS)-3-Methoxy-12-trifluoroacetyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepin-6-ol

Method A (CK-40-2)

3.3 ml of a 0.25 M potassium hydroxide solution (0.045 g (0.81 mmol) indioxane/methanol/water (10/2/5) is mixed with 0.100 g (0.27 mmol) ofN-trifluoroacetylnorgalanthamine and stirred for one hour at roomtemperature. Then, the solution is diluted with 0.4 ml of 2Nhydrochloric acid, and the volatile components are distilled off in arotary evaporator. The residue is taken up with saturated sodiumcarbonate solution and extracted five times with dichloromethane. Thecombined extracts are washed with saturated sodium chloride solution,dried on sodium sulfate, filtered and concentrated by evaporation in arotary evaporator under reduced pressure. 0.070 g of a white-yellowishfoam with a purity of 95% (HPLC, caffeine as an internal standard) isobtained.

Yield: 0.070 g (0.067, 0.25 mmol, 91%), white-yellowish foam(M_(w)=273.3)

Method B (CK-40-3)

A solution that consists of 0.100 (0.27 mmol) ofN-trifluoroacetylnorgalanthamine and 0.243 g (1.35 mmol) of 30% sodiummethanolate-methanol solution in 3 ml of tetrahydrofuran/methanol (1/1)is stirred for three hours at room temperature. The solution isneutralized with 0.7 ml of 2N hydrochloric acid, and the solution isevaporated to the dry state, the residue is taken up with 25 ml ofdichloromethane and washed with saturated sodium carbonate solution andwith saturated sodium chloride solution, dried on sodium sulfate,filtered and concentrated by evaporation in a rotary evaporator underreduced pressure. After drying in a vacuum, a yellowish foam (0.067 g)with a purity of 76% (HPLC, caffeine as an internal standard) isobtained.

Yield: 0.067 g (0.051 g, 0.19 mmol, 69%), white-yellowish foam(M_(w)=273.3)

Method G:

Separation of (+) and (−) Isomers from rac.Norgalanthamine (4)

Production of (−) Norgalanthamine (8)

A solution of 7.72 g (20.0 mmol) of (+)-O,O-di-p-toluoyltartaric acid in15 ml of methanol is added in drops to a solution of 10.92 g (40.0 mmol)of rac.norgalanthamine (4) in 40 ml of methanol and then rewashed with 1ml of methanol. The solution is mixed with a seed crystal and allowed tostand for two days at 4° C. Then, a glass rod is passed vigorouslythrough the solution, and it is allowed to stand for another two to fivedays at 4° C., whereby a glass rod is always passed vigorously throughthe solution again. Then, the precipitated salt is suctioned off,rewashed three times with ice-cold methanol and taken up in 100 ml ofwater. The aqueous phase is made basic with concentrated aqueous ammoniaand extracted three times with 60 ml of ethyl acetate each. The combinedorganic phases are washed once with saturated aqueous sodium chloridesolution, dried (Na₂SO₄, activated carbon), filtered and concentrated byevaporation, by which 2.90 g (37.5% of theory) of colorless crystalswith an angle of rotation of α_(D) ²² [CHCl₃=−62.4 of (−)norgalanthamine (8) is obtained. The methanolic mother liquor isconcentrated by evaporation, the residue is taken up in 100 ml of waterand treated like the pure salt above, by which 4.1 g (53.1% of theory)of crude product can be recovered, which is used as follows forrecovering (+) norgalanthamine.

Production of (+) Norgalanthamine

A solution of 2.9 g (7.5 mmol) of (−)-O,O-di-p-toluoyltartaric acid in5.6 ml of methanol is added in drops to a solution of 4.1 g (15.0 mmol)of recovered norgalanthamine (this is concentrated in (+) isomers) in 21ml of methanol, whereby it is rewashed with 0.5 ml of ethanol. Thesolution is mixed with a seed crystal and treated as in the recovery of(−) norgalanthamine, by which 3.0 g (39% of theory) of colorlesscrystals is obtained with an angle of rotation of α_(D) ²² [CHCl₃]+57.5°(+) norgalanthamine.

As an alternative, (+) norgalanthamine is also obtained by reaction ofrac.norgalanthamine (4) with (−)-O,O-di-p-toluoyltartaric acidanalogously to the above instructions with an angle of rotation of α_(D)²² [CHCl₃]=+60.5°.

EXAMPLE 182

SPH-1534

(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro]3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylicacid triisopropyl silyl ester (CK-9-2)

0.200 g (0.732 mmol) of norgalanthamine (68%(HPLC, CK-1-1)) and 0.47 ml(0.341 g, 3.37 mmol) of triethylamine are introduced at −80° C. in 6 mlof dichloromethane in a single-neck flask with a septum and a CO₂ tank,which is filled by evacuation and flushing with carbon dioxide. Then,the solution is cooled to the point that solid carbon dioxideprecipitates in the reaction solution. After one and one-half hours atabout −80 to −90° C., triisopropyl silyl chloride (0.155 ml, 0.141 g,0.732 mmol) is added via a syringe. Then, the reaction solution isslowly heated overnight to room temperature. In this case, a colorlessprecipitate settles out. The reaction solution is taken up with 10 ml of1N hydrochloric acid, the phases are separated, and the aqueous phase isextracted twice with 10 ml of dichloromethane. The combined organicphases are washed with 10 ml of 1N hydrochloric acid and with 10 ml ofsaturated common salt solution, dried on Na₂SO₄, filtered andconcentrated by evaporation. The yellow viscous oil (0.315 g) ispurified by means of column chromatography on silica gel with the mobilesolvent petroleum ether/ethyl acetate. After concentration byevaporation, 0.208 g of the product is obtained in the form of acolorless foam.

Yield: 0.208 g (0.44 mmol, 60%), colorless foam, (M_(w)=473.7)

TLC: R_(f)=0.35 (petroleum ether/ethyl acetate=1/1)

Melting point: 53-54° C. (petroleum ether/ethyl acetate=1/1)

IR: KBr

v (cm⁻¹) 3556 (m), 3454 (m), 2946 (s), 1679 (s)

¹H-NMR (200.13 MHz, CDCl₃, TMS)

δ 6.60-6.85 (m, 2H), 5.93-6.09 (m, 2H), 4.90 (d, J=15.3 Hz, 0.4H), 4.80(d, J=15.7 Hz, 0.6H), 4.57 (s, 1H), 4.06-4.40 (m, 3H), 3.83 (s, 3H),3.27-3.57 (m, 0.4H), 2.70 (bd, J=16.3 Hz, 1H), 2.41 (bd, J=11.0 Hz,0.6H), 1.60-2.11 (m, 3H), 1.29 (bh, J=5.1 Hz, 3H), 1.05 (d, J=6.8 Hz,8H), 0.98 (d, J=6.9 Hz, 10H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 154.4 and 153.9 (s), 146.5 and 146.2 (s), 144.3 and 144.1 (s), 132.2and 131.8 (d), 129.4 and 129.2 (s), 127.9 (d), 126.5 (d), 121.6 and120.9 (d), 111.1 and 110.9 (d), 88.2 (d), 61.8 (d), 55.8 and 55.7 (q),52.5 and 51.7 (t), 48.3 (s), 46.4 and 45.8 (t), 37.3 and 36.1 (t), 29.7(t), 17.77 17.75, 17.68 and 17.65 (q), 11.9 (d)

EXAMPLE 183

SPH-1535

(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylicacid-tert-butyldiphenylsilyl ester

Analogously to the instructions for theN-triisopropylsilyloxycarbonylnorgalanthamine (TBDP-C1), norgalanthamine(68% (HPLC, CK-1-1)) is reacted with 1 or 1.1 equivalents oftert-butyldiphenylsilyl chloride and 5 equivalents of triethylamine.Then, the reaction is terminated with water or dilute hydrochloric acid,the phases are separated, and the aqueous phase is extracted withdichloromethane. After drying with Na₂SO₄, filtering and concentrationby evaporation, the amorphous foam is purified by means of columnchromatography (silica gel, ethyl acetate/petroleum ether=1/1). Acolorless foam is obtained. Aqueous Yield (M_(w) = Conditions:Working-Up: 524.7): CK- 0.200 g (0.732 10 ml of 1N 0.282 g (0.538 10-1mmol) of hydrochloric mmol, 73%) norgalanthamine, acid 0.172 ml (0.181g, 0.732 mmol) of TBDP-C1 CK- 0.200 g (0.732 10 ml of 0.196 g (0.37 10-2mmol) of distilled water mmol, 51%) norgalanthamine, 0.172 ml (0.181 g,0.732 mmol) of TBDP-C1 CK- 0.400 g (1.46 mmol) 20 ml of 0.3 M 0.505 g(0.96 10-3 of norgalanthamine, hydrochloric mmol, 66%) 0.38 ml (0.398 g,acid 1.606 mmol) of TBDP-C1

TLC: R_(f)=0.40 (petroleum ether/ethyl acetate=1/1)

Melting point: 71-80° C. (petroleum ether/ethyl acetate=1/1)

IR: KBr

v (cm⁻¹) 3553 (m), 3454 (bm), 2932 (s), 1686 (s) 1625 (m)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 7.20-7.68 (m, 10H), 6.56-6.77 (m, 2H), 4.83-5.03 (m, 1H), 5.03 (s,1H), 4.02-4.40 (m, 3H), 3.83 (s, 3H), 3.63 (bt, J=13.1 Hz, 0.3H), 3.41(bf, J=12.9 Hz, 0.7H), 2.70 (bt, J=15.6 Hz, 1H), 2.41 (bd, J=19.7 Hz,1H), 1.78-2.10 (m, 2H), 1.54-1.76 (m, 1H), 1.05 (s, 9H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 153.7 and 153.2 (s), 146.6 and 146.1 (s), 144.4 and 144.2 (s), 135.0and 134.7 (d), 132.4 and 132.3 (s), 132.4 (s), 132.3 and 131.8 (s),129.7 and 129.6 (d), 129.2 and 129.0 (s), 126.5 (s), 121.8 and 121.2(d), 111.1 and 110.9 (d), 88.3 and 88.1 (d), 61.8 (d), 55.9 (q), 52.7and 51.8 (t), 48.3 (s), 46.5 and 46.1 (t), 37.4 and 35.8 (t), 29.7 (t),27.0 and 26.9 (q), 19.1 and 18.9 (d)

EXAMPLE 184

SPH-1536

(4aS,6R,8aS)-3-Methoxy-12-trifluoroacetyl-5,6,9,10,11,12-hexahydro-4aH-[1]benzofuro[3a,3,2-ef]-[2]benzazepin-6-ol

Method A (CK-32-1)

A solution that consists of 5 ml of dichloromethane and 4.6 ml (3.333 g,32.9 mmol) of trifluoroacetic acid anhydride is added in drops at 0° C.within 15 minutes to a solution of 1.00 g (3.66 mmol) of norgalanthamine(68% (HPLC, CK-1-1)), 1.5 ml (1.095 g, 10.8 mmol) of triethylamine in 5ml of absolute dichloromethane. Then, the solution is stirred for 1.75hours at 0° C., and the reaction is then terminated by adding 5.5 ml of2N hydrochloric acid. The phases are separated, and the aqueous phase isextracted three times with 20 ml of dichloromethane in each case. Thecombined organic phases are washed with 30 ml of saturated common saltsolution, dried on Na₂SO₄, filtered and concentrated by evaporation. Thecrude product (0.866 g) is purified by means of MPLC (silica gel, h=25cm, d=3.6 cm, v 300 nm, mobile solvent petroleum ether/ethyl acetate2/1). After concentration by evaporation and drying in a vacuum, theproduct is obtained as a white-yellowish foam (0.866 g).

Yield: 0.866 g (1.95 mmol, 53%), white-yellowish foam, M_(w) =369.3

Method B (CK-32-2)

2.52 g of norgalanthamine (≈90%, 2.268 g, 8.30 mmol) and 3.45 ml (2.520g, 24.9 mmol) of triethylamine are dissolved in 20 ml of absolutedichloromethane. Then, a solution that consists of 1.211 ml (1.830 g,8.71 mmol) of trifluoroacetic acid anhydride and 10 ml ofdichloromethane is added in drops within 30 minutes at 0° C. It isheated to room temperature, additional trifluoroacetic acid anhydride(1.2 ml, 1.830 g, 8.71 mmol) is added in portions, and the reactionsolution is stirred overnight. The solution is diluted with 120 ml ofethyl acetate and washed with 50 ml of 1N hydrochloric acid in eachcase, with 50 ml of saturated NaHCO₃ solution and twice with 50 ml ofsaturated common salt solution in each case, dried on Na₂SO₄ andfiltered. After the concentration by evaporation, the residue isdissolved in 150 ml of dichloromethane, and 141.1 g of a 5% NH₃ solutionis added. The two-phase solution is vigorously stirred at roomtemperature. After 30 minutes, the phases are separated, and the aqueousphase is extracted with dichloromethane (twice, 50 ml). The combinedorganic phases are washed with 1N hydrochloric acid (twice, 50 ml) andwith saturated common salt solution (twice, 50 ml), dried on Na₂SO₄,filtered and concentrated by evaporation. The residue (2.77 g) ispurified by means of MPLC (450 g of silica gel, v=300 nm, mobile solventpetroleum ether/ethyl acetate=1/1). After concentration by evaporationand drying in a vacuum, the product is obtained as a white-yellowishfoam (2.6171 g).

Yield: 2.6171 g (7.09 mmol, 85%), white-yellowish foam (M_(w)=369.3)

TLC: R_(f)=0.23 (petroleum ether/ethyl acetate=1/1)

Melting point: 65-68° C. (petroleum ether/ethyl acetate=1/1)

IR: KBr

v (cm⁻¹) 3546.3 (v), 3417 (by), 2924 (m), 1690 (s)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 6.62-6.92 (m, 2H), 5.88-6.16 (m, 2H), 5.25 (d, J=15.2 Hz, 0.5H), 4.85(d, J=16.6 Hz, 0.5H), 4.42-4.77 (m, 2H), 4.02-4.34 (m, 2H), 3.84 (s,3H), 3.60-3.83 (m, 0.5H), 3.27-3.50 (m, 0.5H), 2.72 (d, J=16.0 Hz,1.0H), 2.29 (bs, 0.7H), 1.80-2.13 (m, 3H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 156.1 (m), 146.4 and 146 (s), 144.8 and 144.7 (s), δ 132.0 (s), 128.8and 128.5 (d), 126.6 and 126.1 (s), 125.7 and 125.3 (d), 120.9 and 119.1(d), 121.9 (q, J=288 Hz), 111.3 (d), 88.1 and 88.0 (d), 61.6 (d), 55.8(q), 52.6 and 51.8 (t), 47.9 (s), 46.5 and 46.3 (t), 38.4 and 35.4 (t),29.64 and 29.58 (t)

EXAMPLE 185

SPH-1537

(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylicacid allyl ester

Variant A (CK-17-1)

3.000 g (11.0 mmol) of norgalanthamine is introduced at 0° C. into asolution that consists of 10 ml of absolute dichloromethane and 4.6 ml(3.333 g, 32.9 mmol) of triethylamine. At 0° C., a solution thatconsists of 1.454 g (12.1 mmol) of allyl chloroformate and 5 ml ofabsolute dichloromethane is added in drops within 20 minutes. Thereaction solution is stirred overnight and in this case heated to roomtemperature. The reaction solution is taken up with 50 ml of 1Nhydrochloric acid and 50 ml of dichloromethane. The phases areseparated, and the aqueous phase is extracted three times with 50 ml ofdichloromethane in each case. The combined organic phases are washedwith 100 ml of saturated common salt solution, dried on Na₂SO₄, filteredand concentrated by evaporation. The crude product (3.2 g) is separatedby means of MPLC (silica gel, h=25 cm, d=3.6 cm, v=200 nm, mobilesolvent petroleum ether/ethyl acetate=2/1). After concentration byevaporation and drying in a vacuum, the product is obtained as awhite-yellowish foam (2.594 g) and 0.232 g of a by-product, which wasidentified as N,O-diallyloxycarbonylnorgalanthamine.

Yield: 2.594 g (7.26 mmol, 66%)

TLC: R_(f)=0.30 (petroleum ether/ethyl acetate=1/1)

Melting point: 44-46° C. (petroleum ether/ethyl acetate=1/1)

IR: KBr

v (cm⁻¹) 3550 (m), 3458 (m), 1700 (s)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 6.62-6.86 (m, 2H), 5.95-6.09 (m, 2H), 5.76-5.94 (m, 1H), 5.10-5.33 (m,2H), 4.93 and 4.83 (d and d, J=15.1 Hz, and J=15.7 Hz, 1H), 4.45-4.68(m, 3H), 4.05-4.44 (m, 3H), 3.83 (s, 3H), 3.27-3.55 (m, 1H), 2.70 (bdd,J=15.1 Hz, and J=15.7 Hz, 1H), 2.26 (bs, 0.5H), 1.93-2.11 (m, 1H),1.69-1.92 (m, 1H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 155.1 and 155.0 (s), 146.4 (s), 144.3 (s), 132.7 (d), 132.3 and 132.0(s), 129.1 (s), 128.0 (d), 126.2 (d), 121.4 and 120.8 (d), 117.3 and116.7 (t), 111.1 and 110.9 (d), 88.1 and 88.0 (d), 65.9 and 65.8 (t),61.7 (d), 55.7 (q), 51.8 and 51.3 (t), 48.2 (s), 45.8 and 45.3 (t), 37.2and 36.3 (t), 29.7 (t)

EXAMPLE 186

SPH-1538

(4aS,6R,8aS)-6-(2-Allyloxycarbonyloxy)-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef][2]benzazepine-11(12H)-yl)carboxylicacid allyl ester

Colorless wax, (M_(w)=441.5)

TLC: R_(f)=0.51 (petroleum ether/ethyl acetate 1/1)

IR: KBr

v (cm⁻¹) 2947 (m), 1739 (s), 1700 (s)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 6.56-6.81 (m, 2H), 6.22 (d, J=10.3 Hz, 1H), 5.73-6.04 (m, 3H),5.08-5.40 (m, 5H), 4.90 (d, J=15.5 Hz, 0.5H), 4.80 (d, J=15.9 Hz, 0.5H),4.44-4.64 (m, 5H), 4.04-4.43 (m, 2H), 3.82 (s, 3H), 3.24-3.54 (m, 1H),2.78 (bd, J=16.4 Hz, 1H), 1.65-2.21 (m, 3H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 155.0 and 154.8 (s), 154.4 (s), 147.2 (s), 144.1 (s) 132.7 (d), 131.5(d), 130.9 (s), 130.6 (d), 128.9 and 128.8 (s), 122.3 (d), 120.6 and120.1 (d), 118.3 (t), 117.2 and 116.6 (t), 111.5 and 111.3 (d), 85.3(d), 68.1 (t), 66.5 (d), 65.8 and 65.7 (t), 55.8 (q), 51.6 and 51.2 (t),47.8 (s), 45.6 and 45.2 (t), 37.6 and 36.7 (t), 27.5 (t)

Variant B (CK-17-2)

1.000 g (3.66 mmol) of norgalanthamine (68% (HPLC, CK-1-1)), dissolvedin 3 ml of absolute dichloromethane, and 0.441 g (3.66 mmol) of allylchloroformate, dissolved in 2 ml of absolute dichloromethane, arereacted analogously to method A with 1.48 ml (1.448 g, 18.3 mmol) ofpyridine. After aqueous working-up analogously to method A and columnchromatography (50 g of silica gel, mobile solvent petroleum ether/ethylacetate=2/1→1/1), 0.784 g of a colorless foam and 0.214 g of the sameby-product are obtained.

Yield: 0.784 g (2.19 mmol, 60%)

EXAMPLE 187

Steps 1-4 Immobilization of(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro-[3a,3,2-ef][2]benzoazepine-11(12H)-yl)carboxylicAcid Allyl Ester on a Hydroxymethyl-Polystyrene Resin (Merrifield Resin)

In a 5-ml-polyethylene frit that is sealed on both sides, 0.200 g (0.208mmol) of hydroxymethylpolystyrene resin (1.04 mmol/g, Merrifield resin³)is suspended in 3 ml of dichloromethane, and it is shaken for 30 minutesat about 40× per minute. After filtering, 0.095 g (0.832 mmol) ofglutaric acid anhydride, and 178 μl (0.134 g, 1.04 mmol) ofethyldiisopropylamine in 2 ml of dichloromethane are added, and thesuspension is shaken for 16 hours at room temperature at about 40× perminute. The reaction solution is filtered off, and the resin is washedonce with dichloromethane, once with methanol and five times withdichloromethane with 2.5 ml in each case. The resin is subsequentlysuspended in 77 μl (0.075 g, 0.624 mmol) of pivaloyl chloride, 178 μl(0.134 g, 1.04 mmol) of ethyldiisopropylamine in 1.75 ml ofdichloromethane and shaken for six hours at room temperature. Afterfiltering and washing with dichloromethane (1×2.5 ml), tetrahydrofuran(1×2.5 ml) and dichloromethane (5×2.5 ml), the resin is shaken in asolution that consists of 0.230 g (0.624 mmol) ofN-allyloxycarbonylnorgalanthamine, 0.013 g (0.104 mmol) of4-dimethylaminopyridine and 178 μl (0.134 g, 1.04 mmol) ofethyldiisopropylamine in 2 ml of dichloromethane at room temperature.After 22 hours, the reaction is terminated by filtering off the reactionsolution, the resin is washed with dichloromethane (1×2.5 ml), withdimethylformamide (2×2.5 ml) and with dichloromethane (5×2.5 ml), dried,suctioned off and dried overnight in a vacuum at 30 to 50 mbar.

To determine the concentration, an aliquot of resin (0.262 g) in 2.5 mlof methanol/tetrahydrofuran (1/3) is steeped for 30 minutes, filteredand suspended in a solution of 0.168 g (0.933 mmol) of 30% sodiummethanolate-methanol solution in 0.5 ml of methanol and 1.5 ml oftetrahydrofuran. The mixture is shaken for 15.5 hours at roomtemperature, filtered off, and the resin is extracted three times withmethanol/dichloromethane (1/1, 2.5 ml) and three times withdichloromethane (2.5 ml). The combined filtrates are neutralized with 95μl (0.067 g, 1.248 mmol) of trifluoroacetic acid and concentrated byevaporation in a rotary evaporator. The residue is purified by means ofcolumn chromatography (5 g of silica gel, mobile solvent petroleumether/ethyl acetate=1/1). After concentration by evaporation and dryingunder high vacuum, 0.048 g of a colorless, vitreous solid is obtained.

Yield: 0.048 g (0.13 mmol, 65% relative to the degree of substitution ofthe hydroxymethyl resin), ¹H-NMR spectrum identical to the startingmaterial

EXAMPLE 187 Steps 5-8

SPH-1539

1-(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a,3,2-ef]-[2]benzazepine-11(12H)-yl)-6-(4-hydroxy-1-piperidyl)hexan-1-one(CK-36-1)

0.273 g of resin, produced from 0.200 g (0.208 mmol) ofhydroxymethylpolystyrene resin⁷ (1.04 mmol/g) according to theabove-described method A, 0.120 g (0.104 mmol) of Pd(Ph₃P)₁, and 0.292 g(2.08 mmol) of dimedone are shaken in 1.2 ml of tetrahydrofuran in a5-ml-polyethylene frit that is sealed on both sides for six hours atroom temperature at about 40× per minute. The resin is filtered andwashed with dichloromethane (1×2.5 ml), withdichloromethane/methanol/ethyldiisopropylamine (5/4/1) (3×2.5 ml) andfinally with dichloromethane (5×2.5 ml). The resin is subsequently mixedwith a solution that consists of 96 μl (0.133 g, 0.624 mmol) of6-bromocaproyl chloride and 178 μl (0.134 g, 1.04 mmol) ofethyldiisopropylamine in 2 ml of dichloromethane and shaken for fivehours at room temperature. After washing with dimethylformamide (6×2.5ml), the resin is shaken in a solution that consists of 0.210 g (2.08mmol) of 4-hydroxypiperidine and 2 ml of dimethylformamide for twelvehours at room temperature. The resin is washed three times with 2.5 mlof dichloromethane in each case and three times with 2.5 ml oftetrahydrofuran in each case and subsequently suspended in a solution of0.168 g (0.933 mmol) of 30% sodium methanolate-methanol solution in 0.5ml of methanol and 1.5 ml of tetrahydrofuran. After twelve hours at roomtemperature, the resin is filtered and extracted withmethanol/dichloromethane (1/1, 3×2.5 ml) and with dichloromethane (3×2.5ml). The combined filtrates are neutralized with 95 μl (0.067 g, 1.248mmol) of trifluoroacetic acid and concentrated by evaporation in arotary evaporator at about 2 ml volumes. The crude product is purifiedby means of preparative thin-layer chromatography (PSC chromatoplate⁸,mobile solvent dichloromethane/methanol=9/1+3% triethylamine).Triethylammonium trifluoroacetate is then separated from the productfraction that is concentrated by evaporation by means of columnfiltration via aluminum oxide (pH 9-10, mobile solventdichloromethane/methanol=20/1). After concentration by evaporation anddrying under high vacuum, 0.012 g of the product is obtained in the formof a yellowish foam.⁷Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG⁸PSC chromatoplate by Merck, Art. No.: 113 895, 20×20 cm, 1 mm, silicagel 60 F₂₅₄

Yield: 0.012 g (0.025 mmol, 12% relative to the degree of substitutionof the hydroxymethyl resin), white-brownish wax (M_(w)=470.6)

TLC: R_(f)=0.32 (dichloromethane/methanol=8/2+2% triethylamine)

HPLC: t_(Ref)=5.38 minutes, 98.6% (Waters Xterra column, 3.9 mm×100 mm,RP-18, 3.5 μm, 250 nm, 1 ml/minute, acetonitrile/20 mmol of Na₂B₄O₇ inH₂O (20/80 v/v, pH 10)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 6.81-6.88 and 6.61-6.71 (m, 2H), 5.90-6.10 (m, 2H), 4.52-4.75 (m, 2H),4.51 (d, J=16.5 Hz, 1H), 4.15 (bs, 1H), 3.84 (s, 3H), 3.82 (s, 1H),3.40-3.60 and 3.10-3.30 (m, 1H), 2.81-3.03 (m, 2H), 2.70 (bd, J=16.3 Hz,1H), 2.33-2.62 (m, 4H), 1.15-2.30 (M, 21H)

LC/MS: t_(Ref)=8.7 minutes, 98%, (Zorbax SB C 13-column, 2.1 mm×30 mm,RP-18, 3 μm, 0.5 ml/minute,

Methanol/H₂O (40/60 100/0 (v/v) in 2 minutes)

APCI-NI-MS

470

EXAMPLE 188

EXAMPLE 188 Steps 1-7

SPH-1540

(4aS,6R,8aS)-6-Hydroxy-3-methoxy-N¹¹-(1-naphthyl)-5,6,9,10-tetrahydro-4aH-[1]benzofuro-[3a,3,2-ef]-[2]benzazepine-11(12H)-carboxamide

Variant A (CK-41-3), Steps 1, 4 and 6-7

0.228 g (0.212 mmol) of 4-carboxy-1-oxobut-1-yloxymethyl-Merrifieldresin is steeped in a 5-ml-polyethylene frit that is sealed on bothsides for 30 minutes in 3 ml of dichloromethane, and after filtering, itis mixed in a solution of 0.234 g (0.628 mmol) ofN-tert-butoxycarbonylnorgalanthamine, 0.013 g (0.105 mmol) of4-dimethylaminopyridine and 108 μl (0.082 g, 0.628 mmol) ofethyldiisopropylamine in 1 ml of dichloromethane. Then, 97 μl (0.079 g,0.628 mmol) of diisopropylcarbodiimide, dissolved in 1 ml ofdichloromethane, is added, and the suspension is shaken for 24 hours atabout 40× per minute at room temperature. After filtering, the resin issuspended for ten minutes in 2.5 ml of dichloromethane/methanol (1/1)while being shaken, filtered and washed with dichloromethane (5×2.5 ml).The resin is subsequently suspended once for ten minutes and once for 50minutes in each case in 2.5 ml of a solution that consists oftrifluoroacetic acid, dichloromethane, and anisole (25/70/5). Afterfiltering, it is washed with dichloromethane (2×2.5 ml), withdichloromethane/methanol/triethylamine (5/4/1, 3×2.5 ml) and finallywith dichloromethane (5×2.5 ml). The resin is shaken for eleven hours ina solution that consists of 0.208 μl (0.245 g, 1.45 mmol) of1-naphthylisocyanate, 113 μl (0.085 g, 0.657 mmol) ofethyldiisopropylamine and 2 ml of dichloromethane at room temperature.After three cycles of washing in each case with dichloromethane (2.5 ml)and tetrahydrofuran (2.5 ml), the polymer is suspended in a solution of1.88 g (1.045 mmol) of 30% sodium methanolate-methanol solution in 0.4ml of methanol and 1.6 ml of tetrahydrofuran. After the resin was shakenfor 24 hours at room temperature, the resin is filtered and extractedwith methanol/dichloromethane (1/1, 3×2.5 ml) and with dichloromethane(3×2.5 ml). The combined filtrates are neutralized with concentratedhydrochloric acid. The suspension is filtered on a silica gel column (10g, dichloromethane/methanol=9/1), and the filtrate is concentrated byevaporation in a rotary evaporator. The crude product is purified bymeans of preparative thin-layer chromatography (silica gel, mobilesolvent dichloromethane/methanol=4//3). After concentration byevaporation and drying under high vacuum, 0.091 g of a yellowish foam isobtained. To remove triethylammonium salts, the residue is taken up indichloromethane and extracted twice with 1N hydrochloric acid and oncewith saturated common salt solution, dried on MGSO₄, filtered andconcentrated by evaporation.

Yield: 0.042 g (0.095 mmol, 45% relative to the degree of substitutionof the 4-carboxy-1-oxobut-1-yloxymethyl-Merrifield resin),brown-yellowish wax (M_(w)=442.5)

TLC: R_(f)=0.21 (dichloromethane/methanol=48/2)

HPLC: t_(Ref)=5.15 minutes, 100% (Merck purospher column 4.0 mm×125 mm,RP-18e, 5 μm, 250 nm, 1 ml/minute, acetonitrile/20 mmol of Cl₃CCO₂H inH₂O (40/60 v/v)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 7.71 (d, J=6.9 Hz, 1H), 7.20-7.66 (m, 6H), 6.85 (d, J=8.4 Hz, 1H),6.63 (d, J=8.2 Hz, 1H), 5.96 (bs, 2H), 4.91 (d, J=16.7 Hz, 1H),4.25-4.62 (m, 3H), 4.09 (bs, 1H), 3.78 (s, 3H), 3.25-3.50 (m, 2H),2.55-2.67 (m, 1H), 1.87-2.04 (m, 2H), 1.60-1.75 (m, 1H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 155.7, 146.9, 144.6, 134.4, 133.8, 132.5, 129.0, 128.7, 128.1, 128.0,126.3, 125.6, 125.5, 124.8, 122.1, 120.7, 111.0, 88.2, 62.9, 55.9, 51.8,48.3, 46.1, 36.4, 29.7

Variant B, Steps 2-5 and 7

0.250 g (0.233 mmol) of 4-carboxy-1-oxobut-1-yloxymethyl-Merrifieldresin is introduced into a frit reactor of synthesis robot (Syro IIMultiSynTech). Then, the resin is steeped in a reactor for 30 minutes indichloromethane, suctioned off, washed three times with dichloromethaneand mixed successively with 0.150 g (1.163 mmol) ofethyldiisopropylamine in 1 ml of dichloromethane and 0.084 g (0.698mmol) of pivaloyl chloride in 1.5 ml of dichloromethane. After six hoursof stirring at 23° C., the solution is suctioned off, and the polymer iswashed in each case with 3 ml of dichloromethane (6×2 minutes). Afterthe addition of 0.260 g (0.698 mmol) ofN-tert-butoxycarbonylnorgalanthamine, 0.014 g (0.116 mmol) of4-dimethylaminopyridine and 0.150 g (1.163 mmol) ofethyldiisopropylamine in 2.5 ml of dichloromethane, the suspension isstirred at 23° C. for 15 hours. After suctioning off, the resin isstirred in 2.5 ml of dichloromethane/methanol (1/1) for ten minutes,suctioned off, washed three times with dichloromethane/methanol (1/1) (3ml, 2 minutes) and five times with dichloromethane (3 ml, 2 minutes).The polymer is subsequently suspended once for ten minutes and once for50 minutes in each case in 2.5 ml of a solution that consists oftrifluoroacetic acid, dichloromethane and anisole (25/70/5). Aftersuctioning off, it is washed with dichloromethane (3×3 ml), withdichloromethane/methanol/triethylamine (5/4/1, 3×3 ml) and finally withdichloromethane (5×) in each case for two minutes. Then, the residue ismixed with 0.197 g (1.163 mmol) of 1-naphthylisocyanate, 0.150 g (1.163mmol) of ethyldiisopropylamine and 2.5 ml of dimethylformamide andstirred for six hours at 50° C. The reaction is terminated by thesolution being suctioned off, the resin being washed with 3 ml ofdichloromethane at 23° C. six times for two minutes in each case, andthe resin being suctioned off in the dry state at 40° C. for tenminutes. For cleavage, the resin is transferred into a 5-ml-polyethylenefrit that is sealed on both sides and steeped in 2.5 ml oftetrahydrofuran for 30 minutes. After filtering, the polymer issuspended in a solution that consists of 0.209 g (1.163 mmol) of 30%sodium methanolate-methanol solution in 0.75 ml of methanol and 1.25 mlof tetrahydrofuran, and it is shaken for 15 hours at about 40× perminute at room temperature. The resin is filtered and extracted threetimes with methanol/dichloromethane (1/1, 2.5 ml) and three times withdichloromethane (2.5 ml). The combined extracts are neutralized withconcentrated hydrochloric acid, filtered and concentrated byevaporation. Then, the crude product is purified by means of columnchromatography on 10 g of silica gel (mobile solventdichloromethane/methanol=99/1). After concentration by evaporation anddrying in a vacuum, 0.029 g of a rose-colored wax with a purity of 75%(HPLC), identical to the product that is produced according to method A,is obtained.

Yield: 0.029 g (0.021 g, 0.047 mmol, 20% relative to the degree ofsubstitution of the 4-carboxy-1-oxobut-1-yloxymethyl-Merrifield resin)

HPLC: t_(Ref)=14.32 minutes, 75% (Merck purospher column 4.0 mm×125 mm,RP-18e, 5 μm, 250 nm, 1 ml/minute, acetonitrile/20 mmol of Cl₃CCO₂H inH₂O (30/70 v/v)

EXAMPLE 189

SPH-1541

Steps 1-2(4aS,6,R,8aS)-3-Methoxy-11-tert-butoxycarbonyl-5,6,9,10-tetrahydro-4aH-[1]benzofuro[3a/3,2-ef][2]benzazepine-6(12H)-yloxy)-5-oxopentanoicacid (CK-48-1)

5.000 g (18.295 mmol) of norgalanthamine (98% (HPLC)) and 3.804 ml(2.777 g, 27.442 mmol) of triethylamine in 75 ml of absolutedichloromethane are introduced at 0° C. While being stirred, a solutionthat consists of 4.393 g (20.124 mmol) of di-tert-butyldicarbonate isadded in drops within 15 minutes at 0° C. After 40 minutes at 0° C., thereaction solution is stirred for three days at room temperature. Aftertwo days, 1.598 g (7.318 mmol) of di-tert-butyldicarbonate and 1.27 ml(0.926 g, 9.147 mmol) of triethylamine are added again. The reactionsolution is taken up with 150 ml of dichloromethane, and the organicphase is washed three times with 100 ml of 1N hydrochloric acid in eachcase, three times with 100 ml of a saturated NaHCO₃ solution in eachcase and twice with 100 ml of saturated common salt solution, dried onNa₂SO₄, filtered and concentrated by evaporation under reduced pressure.The residue (7.065 g, 18.9 mmol, 103% raw yield) is dissolved in 75 mlof absolute dichloromethane, and 4.175 g (36.590 mmol) of glutaric acidanhydride, 0.224 g (1.829 mmol) of 4-dimethylaminopyridine and 3.804 ml(2.777 g, 27.442 mmol) of triethylamine are added to this solution. Thesolution is stirred for three days at room temperature. The reaction isterminated by adding 200 ml of diethyl ether and 500 ml of aqueousammonia solution (pH 10-11). The cloudy aqueous phase is separated (poorphase separation, addition of some methanol, optionally before thedichloromethane solution is distilled off) and extracted three timeswith 200 ml of diethyl ether and then set at pH 2 with concentratedhydrochloric acid. In this case, the cloudy solution becomes clear. Theaqueous phase is extracted four times with 400 ml of dichloromethane ineach case. The combined organic extracts are washed three times with 300ml of distilled water in each case and twice with 300 ml of saturatedcommon salt solution, dried on Na₂SO₄, filtered, mixed with 50 ml ofdiisopropyl ether and concentrated under reduced pressure until theproduct crystallizes out. The solution is allowed to stand for a littlewhile and then the crystallized colorless solid is filtered off, whichis dried in a vacuum.

Yield: 7.546 g (15.48 mmol, 84.6% over two stages), colorlesscrystalline solid, (M_(w)=487.6)

TLC: R_(f)=0.45 (petroleum ether/ethyl acetate=1/2)

R_(f)=0.28 (aluminum oxide, petroleum ether/ethyl acetate=1/2)

Melting point: 159-163° C. (dichloromethane/diisopropyl ether=1/1)

IR: KBr

v (cm⁻¹) 3245 (bs), 2978 (s), 1715 (s), 1683 (s)

¹H-NMR: (200.13 MHz, CDCl₃, TMS)

δ 6.53-6.79 (m, 2H), 6.13-6.29 (m, 1H), 5.82-5.97 (m, 1H), 5.33 (1,J=4.9 Hz, 1.0H), 4.87 (d, J=15.6 Hz, 0.3H), 4.67 (d, J=15.7 Hz, 0.7H),4.53 (s, 1H), 3.99-4.38 (m, 2H), 3.83 (s, 3H), 3.19-3.50 (m, 1H), 2.68(d, J=16.0 Hz, 1.0H), 2.40 (t, J=7.3 Hz, 2.0H), 2.39 (t, J=7.0 Hz,2.0H), 2.01-2.17 (m, 1H), 1.93 (qui, J=7.1 Hz, 2.0H), 1.66-1.84 (m, 1H),1.41 (s, 3H), 1.37 (s, 6H)

¹³C-NMR: (50.32 MHz, CDCl₃, TMS)

δ 178.2 (s), 172.6 (s), 154.9 (s), 147.1 (s), 144.0 (s), 131.3 (s),130.5 (d), 129.6 (s), 123.0 (d), 120.2 (d), 111.0 (d), 85.8 (d), 79.9(s), 63.2 (d), 55.8 (q), 51.8 and 51.2 (t), 48.0 (s), 45.2 (t), 37.9 and37.0 (t), 33.4 (t), 32.9 (t), 28.2 (q), 27.5 (t), 19.7 (t)

EXAMPLE 190

SPH-1542

(See Diagram, Step 3)

Immobilization of(4aS,6R,8aS)-6-Hydroxy-3-methoxy-5,6,9,10-tetrahydro-4aH-[1]benzofuro-[3a,3,2-ef][2]benzoazepine-11(12H)-yl)carboxylicacid-tert-butyl Ester on a Hydroxymethyl-Polystyrene Resin (MerrifieldResin) (CK-43-5)

5.00 g (5.2 mmol) of hydroxymethylpolystyrene resin (1.04 mmol/g,Merrifield resin⁹) is stirred in a three-neck glass reactor with a fritthat is recessed in the bottom and a KPG stirrer in 50 ml ofdimethylformamide (300 s⁻¹). After filtering, a solution that consistsof N-tert-butoxycarbonylnorgalanthamine-6-yloxy-5-oxopentanoic acid(7.607 g, 15.6 mmol), 4-dimethylaminopyridine (0.635 g, 5.2 mmol) in 30ml of absolute dimethylformamide is added to the resin. At roomtemperature, a solution that consists of diisopropylcarbodiimide (2.42ml, 1.969 g, 15.6 mmol) and 10 ml of dimethylformamide is then added inportions. After 20 hours of stirring at room temperature, it isfiltered, the resin is washed six times with dichloromethane (40 ml, 5minutes) and once with diethyl ether (40 ml, 5 minutes) and dried in avacuum.⁹Hydroxymethyl resin, D-1160, Bachem Feinchemikalien AG

To determine the concentration, an aliquot of resin (0.2465 g) in apolyethylene frit that can be sealed on both sides in 2.5 ml ofmethanol/tetrahydrofuran (1/4) is steeped for 30 minutes, filtered, andsuspended in a solution of 0.280 g (1.56 mmol) of 30% sodiummethanolate-methanol solution in 0.5 ml of methanol and 2 ml oftetrahydrofuran. The mixture is shaken for nine hours at roomtemperature, filtered off, and the resin is extracted three times withmethanol/dichloromethane (1/1, 2.5 ml) and three times withdichloromethane (2.5 ml). The combined filtrates are neutralized with119 μl (0.178 g, 1.56 mmol) of trifluoroacetic acid and concentrated byevaporation in a rotary evaporator. The residue is taken up in 30 ml ofethyl acetate, washed twice with saturated NaHCO₃ solution (10 ml), withdistilled water (10 ml) and with saturated common salt solution (10 ml),dried on Na₂SO₄, filtered and concentrated by evaporation again. Theresidue (0.080 g) is purified by means of column chromatography (10 g ofsilica gel, mobile solvent petroleum ether/ethyl acetate=1/1→1/2). Afterconcentration by evaporation and drying under high vacuum, 0.0661 g of acolorless, vitreous solid is obtained.

Yield: 0.0661 g (0.177 mmol. A concentration of 0.718 mmol/g, 103% ofthe theoretical maximum concentration¹⁰ thus is calculated), ¹H-NMRspectrum that is identical to the starting material¹⁰=1.04 mmol/g/(1 g+1 g*1.04 mol/g*(487.6 mol/g−18 mol/g)/1000)

HPLC: t_(Ref)=9.18 minutes, 93.8% (270 nm), 97.7% (285 nm), (PhenomenexLuna column, 3.0 mm×50 mm, RP-18, 3.0 μm, 0.5 ml/minute, methanol/20mmol of trichloroacetic acid in H₂O (50/50 v/v)

Step 4

Recycling Excess(4aS,6R,8aS)-3-Methoxy-11-tert-butoxycarbonyl-5,6,9,10-tetrahydro-4aH-[[1]benzofuro[3a,3,2-ef][2]benzazepine-6(12H)-yloxy)-5-oxopentanoicAcid from the Resin Immobilization (CK-51-1)

The filtrate of the reaction solution and the first five dichloromethanefiltrates are combined and washed three times with 100 ml of 1Nhydrochloric acid, three times with 100 ml of distilled water and twicewith saturated sodium chloride solution, dried with Na₂SO₄, filtered andconcentrated by evaporation. The amorphous residue (6.806 g) issuspended in 50 ml of ethanol and 30 ml of distilled water, then 1.97 g(46.9 mmol) of lithium hydroxide monohydrate is added. The suspension isstirred for three days at room temperature. The reaction solution isextracted three times with 100 ml of dichloromethane in each case, andthe combined extracts are extracted in each case three times with 100 mlof 1N hydrochloric acid and twice with 100 ml of saturated common saltsolution. After drying on Na₂SO₄, filtering and concentration byevaporation under reduced pressure, the organic phase produces 5.06 g ofa colorless foam, which contains about 60%N-tert-butoxycarbonylnorgalanthamine according to HPLC. The residue isreacted analogously to the above-described procedure with 0.164 g (1.339mmol) of dimethylaminopyridine, 3.056 g (26.78 mmol) of glutaric acidanhydride and 2.8 ml (2.033 g, 20.09 mmol) of triethylamine in 50 ml ofdichloromethane. The reaction is terminated by the addition of 200 ml ofdiethyl ether and 250 ml of aqueous ammonia solution (pH 10-11). Thecloudy, aqueous phase is separated and extracted twice with 200 ml ofdiethyl ether and then set to pH 2 with concentrated hydrochloric acid.The aqueous phase is extracted three times with 200 ml ofdichloromethane in each case. The combined organic extracts are washedthree times with 200 ml of distilled water in each case and twice with200 ml of saturated common salt solution, dried on Na₂SO₄, filtered,concentrated by evaporation to about 50 ml, mixed with 50 ml ofdiisopropyl ether and further concentrated under reduced pressure untilthe product crystallizes out. The solution is allowed to stand for alittle while, and then the crystallized colorless solid is filtered off,which is dried in a vacuum.

Yield: 4.909 g (10.07 mmol, 96.6% relative to the excess that is used inthe immobilization)

HPLC: t_(Ref)=13.9 minutes, 99.8% (Merck Purospher column, 4.0 mm×125mm, RP-18e, 5 μm, 285 nm, 1 ml/minute, acetonitrile/20 mmol of Cl₃CCO₂Hin H₂O (40/60 v/v, pH 10)

EXAMPLE 192 Step 1 N-(Adamantan-1-yl)-6-bromohexanoic acid amide

Adamantane-1-amine, hydrochloride (2.50 g, 13.3 mmol) andN-ethyldiisopropylamine (3.79 g, 29.3 mmol) are stirred in absoluteCH₂Cl₂ (50 ml) for 15 minutes at room temperature. Then, 6-bromohexanoicacid chloride (3.13 g, 14.7 mmol) in CH₂Cl₂ (10 ml) is added in drops at0° C. and stirred for one hour at room temperature.

It is extracted with 2N HCl (2×50 ml), water (1×50 ml), saturated sodiumbicarbonate solution (2×50 ml) and saturated common salt solution (1×100ml), dried (sodium sulfate/activated carbon), filtered, and the residuethat is obtained after the solvent is removed in a rotary evaporator isrecrystallized from petroleum ether (25 ml)/diisopropyl ether (25 ml),by which the product is obtained in the form of colorless crystals witha melting point of 73-75° C. (3.51 g, 80%)

TLC: CHCl₃:MeOH=9:1, R_(f)=0.9

¹H NMR (CDCl₃): δ 5.43 (b, 1H), 3.33 (t, J=6.0 Hz, 2H), 2.21-1.15 (m,23H);

¹³C NMR (CDCl₃): δ 171.6 (s), 51.4 (s), 41.3 (t), 37.0 (t), 36.1 (t),33.5 (t), 32.2 (t), 29.1 (d), 27.4 (t), 24.6 (t)

Step 2

SPH-1517

N-(Adamantan-1-yl)-6-[(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]-bromohexanoicacid amide, fumarate

Norgalanthamine (1.00 g, 3.66 mmol), N-(adamantan-1-yl)-6-bromohexanoicacid amide (1.20 g, 3.66 mmol) and potassium carbonate (anhydrous,freshly ground, 1.52 g, 11.3 mmol) are stirred in absolute acetonitrile(10 ml) for 8 hours at boiling temperature.

The residue that is obtained after the solvent is removed in a rotaryevaporator is purified by column chromatography (200 g of silica gel,chloroform:methanol: ammonia=96:3:1), by which the product is obtainedas a light yellow foam (1.73 g, 91%).

The conversion into fumarate was carried out analogously to theproduction of MT-311 and MT-407 and yielded the product in the form oflight yellow crystals with a melting point of 109-114° C.

TLC: CHCl₃:MeOH:NH₃=89:10:1, R_(f)=0.6

Microelement analysis (JOS 1763):

C₃₇H₄₂N₂O₉H₂O Cld.: C, 66.03; H, 7.70; N, 4.28 Fnd.: C, 66.27; H, 7.61;N, 4.22

¹H NMR (DMSO-d₆): δ=7.20 (b, 1H), 6.90-6.63 (m, 2H), 6.51 (s, 2H), 6.11(d, J=10.2 Hz, 1H), 5.82 (dd, J=11.4 Hz, J=4.7 Hz, 1H), 4.56 (s, 1H),4.41 (d, J=14.8 Hz, 1H), 4.22-3.86 (m, 2H), 3.76 (s, 3H), 3.62-3.12 (m,3H), 2.81-2.47 (m, 3H), 2.44-1.04 (m, 26H);

¹³C NMR (DMSO-d₆): δ 171.6 (s), 167.4 (s), 146.3 (s), 144.1 (s), 134.7(d), 132.9 (s), 129.0 (d), 126.3 (d), 124.6 (s), 122.0 (d), 111.7 (d),86.7 (d), 59.8 (d), 55.5 (q), 50.7 (t), 50.5 (t), 47.3 (s), 41.1 (t),36.1 (t), 36.0 (s), 32.0 (t), 31.0 (t), 28.9 (d), 26.0 (t), 25.2 (t),24.9 (t)

EXAMPLE 193

Step 1

2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione

1H-Benz[de]isoquinoline-1,3(2H)-dione (10.0 g, 50.7 mmol) in DMF (50 ml)is slowly added in drops at room temperature to a suspension of sodiumhydride (2.33 g, 55.8 mmol of a 55% dispersion, white oil is removed bywashing with absolute petroleum ether) in absolute DMF (50 ml). It isstirred for 30 minutes, heated to 60° C., 1.5 dibromopentane (46.64 g,202.8 mmol) is added once, and it is stirred for 12 hours at thistemperature.

It is filtered, and the residue that is obtained after the solvent isremoved in a rotary evaporator is dispersed between water (200 ml) andether (200 ml). The aqueous phase is extracted with ether (3×50 ml), thecombined organic phases are washed with water (3×200 ml), 2N NaOH (2×100ml) and saturated common salt solution (1×200 ml), dried (sodiumsulfate), and solvent is removed in a rotary evaporator. Excessdibromopentane is separated by distillation (100° C./20 mbar), theresidue is recrystallized from methanol (200 ml), by which the productis obtained in the form of colorless crystals (15.45 g, 88%) of meltingpoint 114-116° C.

TLC: Petroleum ether:ethyl acetate=4:1, R_(f)=0.35

¹H NMR (CDCl₃): δ 8.48 (dd, J=7.0 Hz, J=1.3 Hz, 2H), 8.13 (dd, J=7.0 Hz,J=1.3 Hz, 2H), 8.48 (t, J=7.0 Hz, 2H), 4.21 (t, J=7.6 Hz, 2H), 3.89 (t,J=6.6 Hz, 2H), 1.89 (quintet, J=6.6 Hz, 2H), 1.79-1.43 (m, 4H);

¹³C NMR (CDCl₃): δ 163.8 (s), 133.7 (d), 131.3 (s), 130.9 (d), 127.8(s), 126.7 (d), 122.4 (d), 39.8 (t), 33.5 (t), 32.2 (t), 27.0 (t), 25.5(t)

Step 2

SPH-1496

2-[5-[(4aS,6R,8aS)-4a,5,9,10,11,12-Hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]pentyl]-1H-benz[de]isoquinoline-1,3(2H)-dione,fumarate

Norgalanthamine (1.00 g, 3.66 mmol),2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione (1.15 g, 3.33mmol) and potassium carbonate (anhydrous, freshly gound, 1.15 g, 10.0mmol) are stirred in absolute acetonitrile (10 ml) for 12 hours atboiling temperature.

The residue that is obtained after the solvent is removed in a rotaryevaporator is purified by column chromatography (100 g of silica gel,chloroform:methanol: ammonia=96:3:1), by which the product is obtainedas a light yellow foam (1.58 g, 88%).

The conversion into fumarate was carried out analogously to theproduction of MT-311 and MT-407 and yielded the product in the form oflight yellow crystals with a melting point of 129-134° C.

TLC: CHCl₃:MeOH:NH₃=89:10:1, R_(f)=0.5

Microelement analysis (JOS 1790):

C₃₇H₃₈N₂O₉*1.5H₂O Cld.: C, 65.19; H, 6.06; N, 4.11 Fnd.: C, 65.02; H,5.82; N, 3.98

¹H NMR (DMSO d₆): δ 8.34 (d, J=7.0 Hz, 4H), 7.76 (d, J=7.0 Hz, 2H),6.81-6.49 (m, 4H), 6.07 (d, J=11.4 Hz, 1H), 5.81 (dd, J=11.4 Hz, J=4.7Hz, 1H), 4.49 (s, 1H), 4.29 (d, J=14.0 Hz, 1H), 4.16-3.74 (m, 4H), 3.70(s, 3H), 3.43-3.01 (m, 2H), 2.50 (b, 2H), 2.27 (d, J=14.8 Hz, 1H),2.12-1.88 (m, 2H), 1.78-1.12 (m, 8H);

¹³C NMR (DMSO-d₆) δ 167.3 (s), 163.3 (s), 146.2 (s), 143.8 (s), 134.7(d), 134.2 (d), 132.8 (s), 131.2 (s), 130.6 (d), 128.7 (d), 127.2 (d),127.1 (S), 126.5 (d), 126.1 (s), 121.9 (s), 121.6 (d), 111.5 (d), 86.7(d), 59.8 (d), 56.0 (t), 55.5 (q), 50.7 (t), 50.2 (t), 47.4 (s), 39.5(t), 32.2 (t), 30.9 (t), 27.3 (t), 25.3 (t), 24.1 (t)

EXAMPLE 194 Step 1 6-Bromo-1-(3,4-dimethoxyphenyl)-1-hexanone

6-Bromohexanoic acid chloride (4.9 g, 22.7 mmol) is added in dropswithin 10 minutes at a temperature of 0 to 5° C. to a mixture thatconsists of 1,2-dimethoxybenzene (3.10 g, 22.7 mmol) and aluminumchloride (3.0 g, 22.7 mmol) in absolute carbon disulfide (50 ml). It isheated within 30 minutes to 40° C., and it is stirred for one hour atthis temperature. It is hydrolyzed with 2N hydrochloric acid (20 ml),dispersed between benzene (30 ml) and 2N hydrochloric acid (30 ml), andthe aqueous phase is extracted with benzene (2×15 ml), the combinedorganic phases are washed with 2N hydrochloric acid (3×50 ml), water(1×50 ml), saturated sodium bicarbonate solution (3×50 ml), saturatedcommon salt solution (1×50 ml), dried (sodium sulfate/activated carbon),filtered, and the residue that is obtained after concentration byevaporation in a rotary evaporator recrystallizes from pentane (35 ml),by which the product is obtained in the form of colorless crystals witha melting point of 44-45° C. (3.2 g, 44.7%).

TLC: Petroleum ether:ethyl acetate=4:1; Rf=0.85

¹H NMR (CDCl₃): δ 7.54 (dd, J=1.9 Hz, J=8.9 Hz, 1H) 7.51 (d, J=1.9 Hz,1H), 6.89 (d, J=8.9 Hz, 1H), 3.97 (s, 6H), 3.40 (t, J=6.4 Hz, 2H), 2.92(t, J=7.0 Hz, 2H), 1.90 (quintet, J=6.4 Hz, 2H), 1.73 (quintet, J=7.0Hz, 2H), 1.63-1.48 (m, 2H);

¹³C NMR (CDCl₃): δ 198.6 (s), 153.2 (s), 149.0 (s), 130.2 (s), 122.6(d), 110.1 (d), 110.0 (d), 56.0 (q), 55.9 (q), 37.7 (t), 33.6 (t), 32.6(t), 27.9 (t), 23.6 (t)

Step 2

SPH-1497

1-(3,4-Dimethoxyphenyl)-6-[(4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-6-hydroxy-3-methoxy-6H-benzofuro[3a,3,2-ef][2]benzazepine-11-yl]hexan-1-one,fumarate

Norgalanthamine (1.00 g, 2.66 mmol),6-bromo-1-(3,4-dimethoxyphenyl)-1-hexanone (1.15 g, 3.66 mmol) andpotassium carbonate (anhydrous, freshly ground, 1.15 g, 10.0 mmol) isstirred in absolute acetonitrile (15 ml) for 12 hours at boilingtemperature.

The residue that is obtained after the solvent is removed in a rotaryevaporator is purified by column chromatography (100 g of silica gel,chloroform:methanol: ammonia=96:3:1), by which the product is obtainedas a light yellow foam (1.70 g, 91%).

The conversion into fumarate was carried out according to standardinstructions.

The conversion into fumarate was carried out analogously to theproduction of MT-311 and MT-407 and yielded the product in the form oflight yellow crystals with a melting point of 88-94° C.

TLC: CHCl₃:MeOH:NH₃=89:10:1, R_(f)=0.5

Microelement analysis (JOS 1782):

C₃₅H₄₃NO₁₀*0.5H₂O Cld.: C, 65.00; H, 6.86; N, 2.17 Fnd.: C, 64.81; H,6.64; N, 2.09

¹H NMR (DMSO-d₆): δ δ 7.61 (d, J=8.9 Hz, 1H), 7.43 (s, 1H), 7.01 (d,J=8.9 Hz, 1H), 6.81-6.66 (m, 2H), 6.58 (s, 2H), 6.11 (d, J=11 Hz, 1H),5.82 (dd, J=11 Hz, J=5 Hz, 1H), 4.61-4.33 (m, 2H), 4.20-3.92 (m, 2H),3.84 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 3.62-3.12 (m, 2H), 3.10-2.81(m, 2H), 2.78-2.43 (m, 3H), 2.39-1.86 (m, 5H), 1.78-1.40 (m, 5H),1.38-1.14 (m, 2H);

¹³C NMR (DMSO-d₆) δ 198.5 (s), 167.2 (s), 153.0 (s), 148.6 (s), 146.3(s), 144.2 (s), 134.6 (d), 132.9 (s), 129.7 (s), 129.0 (s), 126.2 (d),124.0 (d), 122.7 (d), 122.1 (d), 111.7 (d), 110.9 (d), 110.2 (d), 86.6(d), 65.0 (d), 59.8 (q), 55.8 (q), 55.5 (q), 50.8 (t), 50.4 (t), 47.3(s), 37.2 (t), 31.9 (t), 31.0 (t), 26.1 (t), 24.7 (t), 23.8 (t), 15.2(t)

1. Compounds of general formula I

in which the substituents have the meanings that are explained below: R₁and R₂ are the same or different and mean: a) hydrogen, F, Cl, Br, I,CN, NC, OH, SH, NO₂, SO₃H, PO₃H, NH₂, CF₃, OSO₂ (CH₂)_(n)CF₃, in which nis equal to 0, 1 or 2, —OSO₂-aryl, —OSO-vinyl or —OSO₂-ethinyl; b) a low(C₂-C₆), optionally branched, optionally substituted (Ar)alkyl,(Ar)alkoxy, cycloalkyl or cycloalkoxy group; c) an amino group, whichoptionally is substituted by one or two identical or different low(C₁-C₆), optionally branched, optionally substituted (Ar)alkyl or(Ar)alkylcarbonyl or (Ar)alkoxycarbonyl groups or by a group that isselected from an optionally substituted pyrrolidine, piperidine,morpholine, thiomorpholine, piperazine, or homopiperazine radical; d) a—COOH, —COO(Ar)alkyl, —CO-amino group, which optionally is substitutedas indicated under c), or a COH(Ar)alkyl group; e) a —(CH₂)nX (in whichX═Br, Cl, F or I), —(CH₂)_(n)OH, —(CH₂)_(n)CHO, —(CH₂)_(n)COOH,—(CH₂)_(n)CN, —(CH₂)_(n)NC, —(CH)_(n)COalkyl, or —(CH₂)_(n)COaryl group,in which n is 1-4; f) a —(CH₂)_(n)vinyl, —(CH₂)_(n)ethinyl, or—(CH₂)_(n)cycloalkyl group in which n is 0, 1 or 2, whereby cycloalkylis an aliphatic ring with 3 to 7 C atoms; g) a C₃-C₆-substituted alkenylgroup (optionally substituted with H, F, Br, Cl, CN, CO₂alkyl, COalkyl,COaryl); h) a C₃-C₆-substituted alkinyl group (optionally substitutedwith H, F, Br, Cl, CN, CO₂alkyl, COalkyl, COaryl); or i) R₁ and R²together mean —CH═CH—CH═CH—, —O(CH₂)_(n)O— (n=1 to 3), —CH═CHA₁-(A₁ isNH, O or S), or —CH₂CH₂-A₁ (A₁ is NH, O or S); R₃ has the same meaningas R], especially OH and OCH₃, or R₂ and R₃ together mean-A₂(CH₂)_(n)A₂-, in which n is 1 to 3 and substituents A₂ are the sameor different and mean NH, O or S; R₄ and R₅ are either a) both hydrogen,or b) one of R₄ and R₅ is hydrogen, an (Ar)alkyl, (Ar)alkenyl or(Ar)alkinyl group, and the other of R₄ and R₅ is i) OR₆, in which R₆means hydrogen, a low (C₂-C₁₀, optionally branched or substituted) alkylgroup or cycloalkyl group, a C₃-C₁₀ substituted silyl group (forexample, triethylsilyl, trimethylsilyl, t-butyldimethylsilyl ordimethylphenylsilyl), a C₂-C₁₀ alpha-alkoxyalkyl group, for exampletetrahydropyranyl, tetrahydrofuranyl, methoxymethyl, ethoxymethyl,2-methoxypropyl, ethoxyethyl, phenoxymethyl or 1-phenoxyethyl; ii)O—CS—NHR₆ (thiourethane), in which R₆ has the meanings indicated aboveunder i); iii) O—CO—NHR₇ with the meaning below:

iv) O—CO—HR₆, in which R₆ has the meanings indicated above under i),especially ester with the substitution pattern of amino acids (bothenantiomers), such as

v) NR₇R₇, in which two substituents R₇ are the same or different andmean hydrogen, a low (C₁-C₄), optionally branched, alkyl group orcycloalkyl group, or substituents R₇ together are —(CH₂)_(n)—, in whichn is 3 to 5; vi) NH—COR₆ (amide), in which R₆ has the meanings indicatedabove under i); vii) S—R₆, in which R₆ has the meaning indicated aboveunder i); viii) SO_(n)R₈, in which n is 0, 1 or 2, and in which R₈ is a(C₁-C₁₀), optionally branched or cyclic, optionally substituted(Ar)alkyl group; G₁: —(CH₂)_(n)—, in which x is 1 or 2; G₂: —(CH₂)_(y),in which y is 0 to 2; G₃: —(CH₂)_(n)—, in which z is 0 to 3, providedthat the sum of x+y+z is at least 2 and at most 4, or in which G₃ iscarbonyl or thiocarbonyl, —CH(OH)— or —C(OH)═; W is: a) CR₁₃R₁₄, inwhich R₁₃ means hydrogen and R₁₄ means —(CH₂)_(n)NR₇R₇, —CO—NR₇R₇ or—COOR₇, in which n is 0 to 2 and R₇ has the above-mentioned meanings, orR₇ and R₇ form a ring via —(CH₂)_(n)—, in which n is 3 to 5, wherebysubstituents R₁₃ and R₁₄ can be exchanged; b) N-Phenyl (optionallysubstituted with fluorine, bromine, chlorine, (C₁-C₄) alkyl, CO₂ alkyl,CN, CONH₂, or alkoxy) means N-thien-2 or 3-yl, or N-fur-2 or 3-yl or anN-1,3,5-triazinyl, whereby the triazine radical can then be substitutedwith Cl, OR₆ or NR₇R₇, and R₆ or R₇ has the meaning indicated above; c)One of the substituents that is presented below

 in which I means no bond or —(CH₂)_(n)—, whereby n=0 to 3, carbonyl,thiocarbonyl, O, S, —SO— or SO₂, R₆ has the meanings that are indicatedabove, and in which, Q is —(CH₂)_(n)-M*-(CH₂)_(m), whereby n=0 to 4 andm=0 to 4 and M* means alkinyl, alkenyl, disubstituted phenyl,disubstituted thiophene, disubstituted furan, disubstituted pyrazine,disubstituted pyridazine, a spacer of one of the formulas presentedbelow, a peptide spacer L or a heterocyclic spacer HS of the formulasbelow,

 in which R₁₅ means the side chain of D-, L-, D,L-aminoacids orunnatural amino acids, and for the case of n>1, R₁₅ in the individualradicals in each case means the same or a different side chain of D-,L-, D,L-amino acids or unnatural amino acids, provided that atom N inaddition to Q is connected in each case to groups G2 and G3 of formulaI; d) a tricyclic substituent (Tr) that is optionally substituted atleast in one place with at least one heterocyclic ring as a ringcomponent and a binding site to a carbon atom of an anellated benzenering thereof, which is connected via a spacer Q and the nitrogen atomthat is adjacent to Q in each case with G₂ and G₃ of the compound offormula I, whereby Q has the meaning that is indicated above under c);or e) —NH—, —O—, —S—, —SO— or —SO₂—.
 2. Compounds of general formula II

in which D means N—H, N-alkyl, N-acyl, oxygen or sulfur, and in whichsubstituents R₁ to R₅, G₁ to G₃ and W have the meanings that areindicated in general formula I.
 3. Compounds of general formula III

in which X—R₁₆ is a substituent, in which X is oxygen or sulfur and R₁₆is hydrogen or a low (C₁-C₁₀), optionally branched, optionallysubstituted (Ar) alkyl group, and in which substituents R₁ to R₅, G₁ toG₃ and W have the meanings that are indicated in general formula I. 4.Compounds of general formula IV

in which R₁₈ and R₁₉ mean hydrogen, alkyl, aryl or aralkyl, and in whichthe C atoms that carry substituents R₁₈ and R₁₉ are linked to oneanother via a single bond or a double bond, and in which substituents R₁to R₅ and G₁ and G₃ have the meanings that are indicated in generalformula I, whereby W means CH or N.
 5. Compound according to claim 1, inwhich substituent R₆ means a triethylsilyl, trimethylsilyl,t-butyldimethylsilyl or dimethylphenylsilyl.
 6. Compound according toclaim 1, in which substituent R₆ means tetrahydropyranyl,tetrahydrofuranyl, methoxymethyl, ethoxymethyl, (2-methoxypropyl),ethoxyethyl, phenoxymethyl or (1-phenoxyethyl).
 7. Compound according toclaim 1, in which R₄ is hydrogen, and R₅ is OH, CN, CO₂-alkyl,CONR_(a)R_(b), in which Ra is hydrogen, a low (C₁-C₆), optionallybranched, cyclic, substituted alkyl group, and R_(b) is hydrogen, a low(C₁-C₆), optionally branched or substituted alkyl group, or R_(a)+R_(b)together are —(CH₂)_(n)—, in which n means 2 to 6, or—(CH₂)_(n)E(CH₂)_(n)—, in which E is the same as NH, N-alkyl, O, or S,and n is 0 to 5, aryl (phenyl or naphthyl), or a 6-heterocycle. 8.Compound according to claim 7, in which the 6-heterocycle is imidazolyl,oxazolyl, isoxazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrimidinyl, pyrazinyl and substituted variants thereof,imidazolinyl, thiazolinyl or oxazolinyl.
 9. Compound according to claim1, in which R₅ has a meaning other than hydrogen, and R₄ is OH. 10.Compound according to claim 1, in which R₄ and R₅ together are carbonyl(═O), hydrazone (═N—NH—R₉, ═N—NR₉R₁₀) or oxime (═N—OR₁₀), in which R₉ ishydrogen, a low (C₁-C₆), optionally branched or cyclic, optionallysubstituted (Ar)alkyl- or (Ar)alkylcarbonyl-, (Ar)alkylcarbonyloxy groupor a sulfonic acid group, such as tosyl or mesyl, and R₁₀ is hydrogen, alow (C₁-C₆), optionally branched or cyclic, optionally substituted(Ar)alkyl- or (Ar)alkylcarbonyl group, a sulfonic acid group, such as atosyl group or mesyl group.
 11. Compound according to claim 1, in whichR₄ and R₅ together are substituents of the type

in which Y₁, Y₂ are the same or different and mean O, S, NH or N—R₉(free valences are in any case hydrogen), in which R₉ is hydrogen, a low(C₁-C₆), optionally branched or cyclic, optionally substituted(Ar)alkyl- or (Ar) alkylcarbonyl-, (Ar)alkylcarbonyloxy group or asulfonic acid group, such as tosyl or mesyl.
 12. Compound according toclaim 11, in which Y₁ is NH and Y₂ is N—R₉, and in which R₄ and R₅ areconnected by —(CH₂)_(n)— (n=2, 3, or 4).
 13. Compound according to claim1, in which G₁ and G₂ together or separately mean: —C(R₁₁R₁₂)—, in whichR₁₁ and R₁₂ mean hydrogen, OH, a low, optionally branched or cyclic,optionally substituted (Ar)alkyl, aryl, (Ar)alkyloxy or aryloxy group ortogether an alkylspiro group (C₃-C₇ spiro ring).
 14. Compound accordingto claim 1, in which G₁ and G₂ together mean

in which m is 1 to
 7. 15. Compound according to claim 1, in whichtricyclic substituent Tr is a condensed benzene ring of general formula


16. Compound according to claim 15, in which ring A is a substitutedbenzene ring.
 17. Compound according to claim 15, in which one of ringsB and C is an optionally substituted heterocyclic ring and the other isa substituted ring that can contain one or more heteroatoms in the ring.18. Compound according to claim 15, in which the benzene ring issubstituted in at least one place, whereby these substituents arehalogens, such as fluorine and chlorine, halo-C₁-C₃ alkyl groups, suchas trifluoromethyl, C₁-C₃ alkyl groups, such as methyl, C₁-C₃ alkoxygroups, such as methoxy, and the hydroxy group, especially a halogen,such as fluorine.
 19. Compound according to claim 15, in which theoptionally substituted heterocyclic ring B or C is a 4- to 14-memberedring, preferably a 5- to 7-membered ring, especially a 5- to 7-membered,nonaromatic ring, which contains one or two identical or differentheteroatoms.
 20. Compound according to claim 19, in which at least oneheteroatom of the heterocyclic ring (1 to 3 heteroatoms are possible) isnitrogen, oxygen, or sulfur.
 21. Compound according to claim 20, inwhich heterocyclic ring B or C is pyridine, pyrazine, pyrimidine,imidazole, furan, thiophene, pyrrolidine, piperidine, hexamethylenimine,tetrahydrofuran, piperazine, morpholine or thiomorpholine.
 22. Compoundaccording to claim 15, in which the 5- to 8-membered ring B or C is a 5-to 8-membered heterocyclic or alicyclic ring, or a carbon ring that issubstituted at least in one place.
 23. Compound according to claim 22,in which the 5- to 8-membered carbon ring is a benzene ring or asaturated or unsaturated ring, for example, benzene, cyclopentane,cyclopentene, cyclohexane, cyclohexene, cyclohexadiene, cycloheptane,cycloheptene and cycloheptadiene.
 24. Compound according to claim 1, inwhich tricyclic substituent Tr is a group from one of the formulas thatis presented below


25. Compound according to claim 1, in which tricyclic substituent Tr isa group from one of the formulas that is presented below


26. Compound according to one of claims 1 to 25 claim 1, in which Tr isa cyclic or bicyclic hydrocarbon.
 27. Compound according to claim 26, inwhich Tr has one of the formulas below:


28. Compound according to claim 1, in which substituent Tr issubstituted at least in one place with R₁, and R₁ has the meaningsindicated in claim
 1. 29. Compound according to claim 1, in whichsubstituent W is nitrogen and/or substituent G₁ is —(CH₂)_(x)—, in whichx is equal to 1 or 2 and G₂ means (CH₂)_(y)—, in which y is equal to 0to 2, provided that x+y together mean at least 2 and at most
 4. 30.Compound according to claim 1, in which substituents G₁ and G₂ togetheror separately have the meaning of —CR₁₁R₁₂—, in which R₁₁ and R₁₂ meanhydrogen, hydroxy, a low, optionally branched or cyclic, optionallysubstituted (Ar)alkyl, aryl, (Ar)alkoxy or aryloxy group.
 31. Compoundaccording to claim 1, in which G₁ and G₂ together are an alkylspirogroup (C₃-C₇ spiro ring).
 32. Process for the production of thecompounds of claim 1, characterized in that the combinatory orparallel-synthesis technology is used, whereby the basic molecule isimmobilized by a functional group (linker) in a solid phase, whichimplements the synthesis of the target compound and then this targetcompound is separated from the solid phase.
 33. Process according toclaim 32, wherein the basic molecule is immobilized in the solid phasevia a carbon center, a nitrogen center or an oxygen center.
 34. Processaccording to claim 32, wherein —X(CH₂)_(n)CO (X═CH₂, CO, O, S, NH),—X(CH₂)_(n)OCO (X═CH₂, CO, O, S, NH), —XC₆H₄CH₂— (═CH₂, CO, O, S, NH),THP, or —X(CH₂)_(n)Si(alkyl)₂ is used as a functional group (linker).35. Process according to claim 32, wherein —X(CH₂)_(n)CO(X═CH₂, O, NH,So₀₋₂), —X(CH₂)_(n)CS (X═CH₂, O, NH, SO₀₋₂), X(CH₂)_(n)JCO (X═CH₂, O,NH, So₀₋₂; J=NH, O, S), or XC₆H₄CH₂ (X═CH₂, O, S) is used as afunctional group (linker).
 36. Process according to claim 32 or 33,wherein —(CH₂)_(n)Si(alkyl)₂-, —C₆H₄Si(alkyl)₂-, —(CH₂)_(n)Sn(alkyl)₂-,—C₆H₄Sn(alkyl)₂, —(CH₂)_(n)S, or —C₆H₄S is used as a functional group(linker).
 37. A pharmaceutical composition comprising at least one ofthe compounds of general formulas I, II, III or IV, or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable vehicle.
 38. (canceled)
 39. Process for the production ofpharmaceutical agents, in which at least one of the compounds of generalformulas I, II, III or IV is mixed with a pharmaceutically acceptablevehicle and/or formulation adjuvant.